Target rev a shelf

Target rev a shelf DEFAULT

Last week, the PS5 restock world was a little on the quiet side. so far this week. The world was largely focused on the Nintendo Switch OLED toward the end of the week, alongside the launch of preorders for Apple's latest Watch, so it's likely there was some space given to those products. That could mean we'll see an increased number of restocks this week, which is what a rumor from Jake Randall seems to suggest regarding Target's plan for this week. Hopefully we will know more about that restock soon. 

We're also looking for a PS5 restock from Walmart and Amazon, which haven't had consoles in a few weeks now. Outside of these places, the most reliable place to get a PS5 recently has been PlayStation Direct. Sony had restocks available on two to three times as many days as most other retailers in September, and that is expected to continue into this month. The key to getting a console through PlayStation Direct is to sign up for emails in your account settings. Sony will email you with a date and time to log on and make your purchase, and as long as you follow those instructions, you should see a console at your front door in no time. 

Want a different way to get your hands on a PS5? We've been tracking all of the places selling both the standard edition and the digital edition of the PS5 for months, helping thousands of people snap up the console when it appears with our tips and shortcuts. Check it out!


Why is the PS5 so tough to find?

There are three big reasons why you're still struggling to get a PS5. The first is the most obvious: The system is really popular. Sony says the PS5 is its best-selling console and has already sold 10 million units since launch. 

The second reason is the current chip shortage impacting most of the world's electronics. Sony did say it has secured enough chips to meet its goal of 14.8 million consoles for the fiscal year. 

As for the last reason, it comes down to bots. Resellers are using software to purchase a massive number of PS5s at once, leaving only a few for actual humans to buy. Retailers added various bot protections during PS5 restocks, but these restrictions only hamper resellers so much.

Where has the PS5 been available lately?

Stock refreshes were thin on the ground earlier this month, though they've accelerated recently. Here's a look at the recent PS5 restock history:

  • Antonline: Aug. 31
  • Walmart: Sept. 16
  • PlayStation Direct: Aug. 24, Sept. 10, 14, 15, 21, 22, 24, 28
  • GameStop: Sept. 14, 28, 30
  • Amazon: Sept. 2, Sept. 21, 27
  • Target: Sept. 10, Oct. 1
  • Best Buy: Sept. 23, Oct. 1, 4

How can I get a PS5 from PlayStation Direct?

The store with the most frequent PS5 restocks is Sony's official store, PlayStation Direct. Drops usually happen at 2 p.m. PT (5 p.m. ET) during the middle of the week (Tuesday, Wednesday, Thursday). What Sony has done lately is give a lucky few email invites for exclusive access to the store, which typically starts at 12 p.m. PT (3 p.m. ET). 

To get one of these special invites, you not only need luck, you also need a PSN account. You can sign up for one on the PSN website and it's free. While signing up, check that you have opted in to all promotional emails in the settings on your PlayStation account. From here, it's a matter of being patient and having a little luck on your side. It appears priority access emails are sent randomly, but you will need to partake in one of the queues on PlayStation Direct in order to be considered. 

PlayStation Direct PS5 restock works a little differently than other retailers. At the start time, there's a welcome page with a countdown clock indicating when the queue will start. You can stay on this page and when time is up, the website will begin placing people in line to buy a PS5. The page will update and say how long you'll have to wait, but it's not a guarantee. To help your chances, once you're in a queue, share the link with your other devices like your phone. Make sure each device uses a different IP address (such as having your phone on its mobile plan while your computer uses your home Wi-Fi). This can improve your chances, as your other device might be put into a different line that moves at a faster pace. Even if you don't get a PS5, as mentioned earlier, you still could get a pass to buy one on the next go-round.

What are some helpful tips for buying a PS5?

Major retailers like Walmart, GameStop, Amazon, Target and Best Buy don't usually give much notice ahead of a restock. Sometimes they'll have a restock in the morning, other times in the afternoon and in some cases, even in the middle of the night. Here are some tips to help you get the jump on the competition. 

First tip: Don't wait until you see an alert for a PS5 inventory drop. Check the links at major retailers for stock updates daily or even multiple times a day. (We've got them all lined up below.) If you do happen upon some PS5 availability, go all-in with as many browsers and devices as possible. On a desktop, for example, open the retailer's page in Chrome, Firefox and Edge. Then do the same on your phone and tablet. The more devices and browsers, the better. It's like with lottery tickets: The more you have, the better your chances of winning.

Second tip: Create accounts at the different retailers and make sure you're already logged in if you're going to try to get a PS5. Make sure all your shipping, bill and payment info is updated on whatever device you can buy from, whether it's a laptop, desktop or phone. This makes checking out a lot faster, which is crucial as retailers' sites get quickly bogged down, leading to people losing their chance of securing a PS5. 

Third tip: Keep checking back with this post and follow CNET and Oscar Gonzalez on Twitter for updates.

How can I get early access to a PS5 restock?

While most retailers very much want you to show up when something is marked in stock, the extended difficulty in getting a PS5 has encouraged Best Buy and GameStop to offer early access to sales for its paid members. 

The recently expanded Totaltech program from Best Buy offers a ton a benefits for its $200 per year price tag, but the big one for would-be PS5 owners is early access to "hot products during the holiday season" which means there will be limited access events where you could get a PS5 without having to click refresh on your browser because you're in a member's only queue.

If you want to increase your chances of getting a PS5 from GameStop, all you need to do is sign up for the PowerUp Rewards Pro program. This is a subscription program GameStop has had for years, and it uses this program to offer discounts and coupon codes as well as a subscription to Game Informer magazine. This program costs $20 per year, and if GameStop is true to its promise people who are a part of this program will be able to get a PS5 before it is available to everyone on the website. 

Where else can I buy a PS5 if I'm willing to pay extra?

If you're starting to crack and considering buying a PS5 right now (and we know that with the number of big PS5 games about to drop over the next few months, the pressure is on), you can do so, but at the cost of a hefty markup on sites like eBay or StockX. On eBay, for example, we've seen PS5 units priced over $1,000, although prices have slowly made their way down to approximately $700. 

Where to buy a PlayStation 5


You can check inventory on the $400 Digital Edition at Walmart by clicking the button below, or you can try to snag the pricier PS5 with Blu-ray for $500.


storage disk show


The following example displays information about all disks:

cluster1::> storage disk show Usable Container Disk Size Shelf Bay Type Position Aggregate Owner ---------------- ---------- ----- --- ----------- ---------- --------- -------- 1.1.1 10GB 1 1 spare present - node1 1.1.4 78.59GB 1 4 spare present - node1 1.1.12 10GB 1 12 spare present - node1 1.2.12 10GB 2 12 broken present - node1 1.3.7 78.59GB 3 7 aggregate parity aggr0_u23 node1 1.1.6 78.59GB 1 6 broken present - node1 1.2.10 78.59GB 2 10 aggregate dparity aggr0_u23 node1 1.4.9 78.59GB 4 9 aggregate data aggr0_u23 node1 1.1.0 10GB 1 0 aggregate dparity aggr0_u22 node2 1.4.1 10GB 4 1 aggregate data dp_degraded node2 1.1.2 10GB 1 2 spare present - node2 1.1.3 20GB 1 3 spare present - node2 1.4.4 20GB 4 4 spare present - node2 1.4.6 10GB 4 6 aggregate data dp_sdc node2 1.1.5 268.0GB 1 5 maintenance present - node2 1.3.0 10GB 3 0 aggregate parity aggr0_u22 node2 1.4.11 10GB 4 11 spare present - node2 1.4.13 20GB 4 13 broken present - node2 [...]

The following example displays detailed information about a disk named 1.0.75

cluster1::> storage disk show -disk 1.0.75 Disk: 1.0.75 Container Type: spare Owner/Home: node2 / node2 DR Home: - Stack ID/Shelf/Bay: 1 / 0 / 75 LUN: 0 Array: N/A Vendor: NETAPP Model: X267_HKURO500SSX Serial Number: ZAKAS0GH UID: 1FF17846:0A419201:9325845A:3ABD5075:00000000:00000000:00000000:00000000:00000000:00000000 BPS: 512 Physical Size: 10.

The following example displays RAID-related information about disks used in an aggregate:

cluster1::> storage disk show -raid-info-for-aggregate Owner Node: node1 Aggregate: aggr0_node1_0 Plex: plex0 RAID Group: rg0 Usable Physical Position Disk HA Shelf Bay Chan Pool Type RPM Size Size -------- --------------------- ------------ ---- ------ ----- ------ -------- -------- data 2.11.2 2d 11 2 B Pool0 SAS 15000 9.77GB 9.93GB dparity 2.11.0 2d 11 0 B Pool0 SAS 15000 9.77GB 9.93GB parity 2.11.1 2d 11 1 B Pool0 SAS 15000 9.77GB 9.93GB Owner Node: node2 Aggregate: a1 Plex: plex0 RAID Group: rg0 Usable Physical Position Disk HA Shelf Bay Chan Pool Type RPM Size Size -------- --------------------- ------------ ---- ------ ----- ------ -------- -------- data 2.1.8 2a 1 8 B Pool0 BSAS 7200 9.77GB 9.91GB dparity 2.1.6 2a 1 6 B Pool0 BSAS 7200 9.77GB 9.91GB parity 2.1.7 2a 1 7 B Pool0 BSAS 7200 9.77GB 9.91GB Owner Node: node2 Aggregate: a1 Plex: plex0 RAID Group: rg1 Usable Physical Position Disk HA Shelf Bay Chan Pool Type RPM Size Size -------- --------------------- ------------ ---- ------ ----- ------ -------- -------- data 2.1.11 2a 1 11 B Pool0 BSAS 7200 9.77GB 9.91GB dparity 2.1.9 2a 1 9 B Pool0 BSAS 7200 9.77GB 9.91GB parity 2.1.10 2a 1 10 B Pool0 BSAS 7200 9.77GB 9.91GB Owner Node: node2 Aggregate: aggr0 Plex: plex0 RAID Group: rg0 Usable Physical Position Disk HA Shelf Bay Chan Pool Type RPM Size Size -------- --------------------- ------------ ---- ------ ----- ------ -------- -------- data 2.1.5 2a 1 5 B Pool0 BSAS 7200 9.71GB 10.03GB dparity 2.1.2 2a 1 2 B Pool0 BSAS 7200 9.71GB 10.03GB parity 2.1.4 2a 1 4 B Pool0 BSAS 7200 9.71GB 10.03GB 12 entries were displayed.

The following example displays RAID-related information about spares:

cluster1::> storage disk show -spare Original Owner: node1 Checksum Compatibility: block Usable Physical Disk HA Shelf Bay Chan Pool Type RPM Size Size Owner --------------- ------------ ---- ------ ----- ------ -------- -------- -------- 1.1.23 0b 1 23 A Pool0 FCAL 10000 132.8GB 134.2GB node1 1.1.25 0b 1 25 A Pool0 FCAL 10000 132.8GB 133.9GB node1 1.1.26 0b 1 26 A Pool1 FCAL 10000 132.8GB 133.9GB node1 1.1.27 0b 1 27 A Pool1 FCAL 10000 132.8GB 134.2GB node1 Home Owner: node2 Checksum Compatibility: block Usable Physical Disk HA Shelf Bay Chan Pool Type RPM Size Size Owner --------------- ------------ ---- ------ ----- ------ -------- -------- -------- 1.1.19 0a 1 19 B Pool1 FCAL 10000 132.8GB 133.9GB node2 1.1.20 0a 1 20 B Pool0 FCAL 10000 132.8GB 133.9GB node2 1.1.21 0a 1 21 B Pool0 FCAL 10000 132.8GB 133.9GB node2 [...]

The following example displays RAID-related information about broken disks:

cluster1::> storage disk show -broken Original Owner: node1 Checksum Compatibility: block Usable Physical Disk Outage Reason HA Shelf Bay Chan Pool Type RPM Size Size --------------- ------------- ------------ ---- ------ ----- ------ -------- -------- 1.1.0 admin failed 0b 1 0 A Pool0 FCAL 10000 132.8GB 133.9GB 1.2.6 admin removed 0b 2 6 A Pool1 FCAL 10000 132.8GB 134.2GB Original Owner: node2 Checksum Compatibility: block Usable Physical Disk Outage Reason HA Shelf Bay Chan Pool Type RPM Size Size --------------- ------------- ------------ ---- ------ ----- ------ -------- -------- 1.1.0 admin failed 0a 1 0 B Pool0 FCAL 10000 132.8GB 133.9GB 1.1.13 admin removed 0a 1 13 B Pool0 FCAL 10000 132.8GB 133.9GB 4 entries were displayed.

The following example displays RAID-related information about disks in maintenance center:

cluster1::> storage disk show -maintenance Original Owner: node1 Checksum Compatibility: block Usable Physical Disk Outage Reason HA Shelf Bay Chan Pool Type RPM Size Size --------------- ------------- ------------ ---- ------ ----- ------ -------- -------- 1.1.8 admin testing 0b 1 8 A Pool0 FCAL 10000 132.8GB 133.9GB 1.2.11 admin testing 0b 2 11 A Pool1 FCAL 10000 132.8GB 134.2GB Original Owner: node2 Checksum Compatibility: block Usable Physical Disk Outage Reason HA Shelf Bay Chan Pool Type RPM Size Size --------------- ------------- ------------ ---- ------ ----- ------ -------- -------- 1.2.10 admin testing 0a 2 10 B Pool1 FCAL 10000 132.8GB 133.9GB 1.2.13 admin testing 0a 2 13 B Pool1 FCAL 10000 132.8GB 134.2GB 4 entries were displayed.

The following example displays partition-related information about disks:

cluster1::> storage disk show -partition-ownership Disk Partition Home Owner Home ID Owner ID -------- --------- ----------------- ----------------- ----------- ----------- VMw-1.13 Container pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 VMw-1.14 Container pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 VMw-1.15 Container pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 Root pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 Data pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 VMw-1.16 Container pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 Root pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 Data1 pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 Data2 pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 VMw-1.17 Container pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 VMw-1.18 Container pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 Root - - - - Data pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 VMw-1.19 Container pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 Root pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786 Data1 - - - - Data2 pvaruncluster-2-01 pvaruncluster-2-01 4087518786 4087518786
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  • After researching and reassessing over 50 baby formulas, we’ve updated this guide with five we recommend.

  • After researching and reassessing over 50 baby formulas, we’ve updated this guide with five we recommend.

    Kirkland Signature ProCare Non-GMO Infant Formula, Sam’s Club’s Member’s Mark Infant, Target’s Up & Up Advantage Infant Formula, and Parent’s Choice Tender Infant Formula are all generic formulas that our research shows are just as nutritious as brand-name versions, but much less expensive. We also recommend Earth’s Best Organic Infant Formula.

    We’ve updated this guide with new information about understanding formula ingredients, what to know about European formulas, and other guidance on choosing a baby formula.

    We've also updated this guide to reflect that Bobbie offers free shipping if you subscribe to receive monthly shipments of their formula. Without the subscription, shipping costs between $8 and $25, depending on how many cans you purchase.

March 15, 2021

No matter how you do it, feeding a baby is hard work. If you’re using formula, there are the added challenges of deciphering long lists of ingredients and distinguishing among the dozens of brands and types. And formulas can differ drastically in cost, which can create more confusion, not to mention worry.

We spent more than 60 hours researching formulas, interviewing pediatricians and other experts, and reading more than 20 scientific studies and journal articles. And we learned that all FDA-approved formulas made for healthy, full-term infants are safe and nutritionally adequate for normal growth and development from birth through the first year. We then analyzed the ingredients of more than 55 formulas to find the ones we think offer the best combination of evidence-backed benefits and value.

We recommend Costco’s Kirkland Signature ProCare Non-GMO Infant Formula, Sam’s Club’s Member’s Mark Infant, and Target’s Up & Up Advantage Infant Formula, all generic options that are just as nutritious as brand-name versions, but much less expensive. We also recommend the generic Parent’s Choice Tender Infant Formula (the least expensive true “gentle” formula we’ve found) and Earth’s Best Organic Infant Formula (an affordable organic formula). And we have information about an FDA-regulated “European-style” formula, as well as what to know about so-called toddler formula for older babies (hint: medical experts say it’s unnecessary).

Babies can have individual needs. Consider these recommendations as a starting point, and check out our full list of formulas for even more options. If you’re looking for other baby-feeding gear, consult our guide to the best baby bottles (and bottle brush).

Because traditional formulas are all required to meet the same basic nutritional standards, we looked for the most affordable formulas that offer the most additional potential benefits. Costco’s Kirkland Signature ProCare Non-GMO Infant Formula (about 50¢ per ounce, and slightly less if you’re a Costco member) uses lactose, the sugar naturally found in breast milk. And this formula provides many of the same extra nutrients you’ll find in formulas that cost two or three times as much.

Sam’s Club’s Member’s Mark Infant (around 50¢ per ounce, and a little less if you’re a Sam’s Club member) includes expert-recommended ingredients, such as lactose (the carbohydrate found in breast milk), as well as a few desirable extras. This formula is also sold as Up & Up Infant, Parent’s Choice Premium Infant, and Mama Bear Infant, among others, so it’s easy to find.

Though slightly more expensive than our main picks, Up & Up Advantage (around 60¢ per ounce) is still one of the least expensive formulas we found. Unlike our main picks, this formula is available in a smaller, 35-ounce size. It’s also sold in grocery and drugstore chains, as CVS Advantage, Sam’s Club Advantage, and Walgreens Advantage, among others, as well as online as Amazon’s Mama Bear Advantage, so it’s also easy to find.

Most babies do well on traditional formula, but if your pediatrician recommends giving your baby a “gentle,” “tender,” or partially hydrolyzed formula (containing partly broken-down milk proteins, which may be easier for some babies to digest), we suggest the generic Parent’s Choice Tender (around 60¢ per ounce). At two-thirds the price of name brand formulas, it’s the cheapest partially hydrolyzed formula we found. But it has many of the same potentially beneficial additives as much more expensive brands.

If you want a formula made from USDA-certified organic ingredients, we recommend Earth’s Best Organic Infant Formula (around $1.15 per ounce). It’s the least expensive organic formula we found that has lactose as its only carbohydrate, and it contains extra nutrients.

Why you should trust us

We read more than a dozen scientific studies, journal articles, reports, and advances regarding baby formula in order to understand its ingredients, nutrients, and other components. We looked at information from the FDA and CDC to learn how formula is regulated and tested in the US. Finally, we analyzed the nutrition and ingredients labels of some 50 formulas to understand the differences and similarities among them.

I’m a freelance science writer with a PhD in cell biology from the University of Pittsburgh. I’m also the author of Wirecutter’s guide to the best cloth face masks for kids, and I’ve covered other parenting topics for Undark, Smithsonian, and more. I have three kids, and I’ve experienced the difficulties that come with infant feeding. Also, I’m fascinated by nutrition science. This guide builds on research and reporting from Wirecutter supervising editor Courtney Schley.

What to know about baby formula

Four infant formulas we recommend stacked together.

All babies require either breast milk, baby formula, or a combination of the two during the first year of life.

This guide is intended as an introduction to baby formula. We focused our research on cow’s milk–based formulas for babies who are healthy, were born at full term, and don’t have any specialized nutritional or medical needs. You should talk to your baby’s pediatrician about any concerns related to feeding your baby.

Four major companies manufacture baby formula for sale in the US: Mead Johnson (Enfamil); Abbott Nutrition (Similac); Nestlé (Gerber); and Perrigo (which makes generic formulas sold in many grocery and pharmacy chains and by other brands, including Earth’s Best and Bobbie). Our experts were clear: All infant formula sold in the US and labeled for healthy babies is safe and will support normal growth and development from birth through 12 months. The FDA tightly regulates and monitors baby formula and has strict requirements for its nutrients, ingredients, composition, and manufacturing processes. Regardless of a formula’s brand or type, most of the information on the nutrition label of a can or bottle of formula will be exactly the same.

Generic formulas are just as highly regulated as name-brand formulas, and often the differences between name-brand formulas and generics are minor. “Brand-name and store-name formulas are nearly identical,” a 2017 article on infant feeding in the journal Pediatrics states. Pediatricians Thomas and Porto both told us that parents should feel comfortable using store-brand or generic infant formulas because they contain all of the same FDA-required nutrients and ingredients as formulas made by Enfamil, Similac, and Gerber (whose brands can cost two to three times as much). But if you’re choosing a generic, especially if you’ve had your baby on the name-brand equivalent, it may be worth comparing the ingredients lists.

Within these regulations, formula companies have some latitude with regard to their specific combinations of macronutrients (proteins, carbohydrates, and fats), as well as extra ingredients and nutrients.

Brand-name and store-brand formulas are nearly identical.

Bridget Young, a professor of pediatrics at the University of Rochester who studies infant nutrition, explained that although “all formulas are definitely not the same,” much of what you’ll read on a formula container is “mostly just marketing,” and there’s little reason to select—or avoid—a certain formula based on these claims.

“In terms of ‘this formula is for colic, this formula is for constipation’—all formulas have to meet the needs of all infants in the US, from 0 to 12 months. So you can’t have a formula that’s just for a baby who is also breastfed, or a 2-month-old baby who is constipated,” Young said. You will find some differences among the ingredients lists for various formula types, however: “The marketing does come from somewhere; they do have different ingredients. They’ve either added an ingredient or tweaked an ingredient that they think might help,” she explained.

All infant formula in the US labeled for healthy babies is safe and will support normal growth and development from birth through 12 months.

Young and pediatricians Porto and Thomas all agree that if your baby is feeding well and happily on a certain formula, there’s probably no reason to change it. On the other hand, some formula companies misleadingly suggest that changing brands could be bad for a baby. For example, see Similac’s response to the “frequently asked question” of whether it’s “safe to switch baby formula”: “If you are talking about switching brands of formula, you should know that not all formulas are the same and switching between them may be difficult for your baby to tolerate.” Thomas said this is untrue and that most babies will tolerate changing formula brands and formulations well: “Switching from formula to formula is not a hardship on the baby.”

Some otherwise healthy babies without allergies do have trouble digesting certain formulas and can exhibit gassiness, spit-up, constipation, or fussiness. Porto said it can be hard to determine whether it’s the formula that might be causing trouble for your baby (and, if so, which component of the formula). If the formulas we recommend in this guide aren’t right for your baby, or you’re interested in what makes other formulas different, take a look at our More baby formulas to consider section.

Understanding baby formula labels

The baby formulas we recommend, stacked together with their ingredient lists facing the camera.

There is a dizzyingly long list of potential ingredients in formula, and understanding the label isn’t easy. Many of the ingredients that fulfill the FDA-required vitamins and minerals have complex names (“iron” might be listed as “ferrous sulfate”). And a formula might proclaim it “contains DHA” on the front, but to find it on the ingredients list, you’d need to know that DHA comes from Crypthecodinium cohnii oil. Here, we’ve listed the FDA-required ingredients you’ll find in all US formulas.

Required nutrients, vitamins & minerals

FDA-required nutrientsWhat you’ll read on the label
CarbohydratesLactose, maltodextrin, corn syrup, sugar, sucrose, and/or rice starch
FatsPalm, safflower, soy, coconut, and/or sunflower oils
ProteinNon-fat milk, whey, hydrolyzed whey, milk protein isolate, soy protein
FDA-required vitamins & mineralsWhat you’ll read on the label
CalciumCalcium carbonate, calcium chloride, or calcium hydroxide
CholineCholine bitartrate
CopperCupric sulfate
FolateFolic acid
IodinePotassium iodide
IronFerrous sulfate
Linoleic acidLinoleic acid
ManganeseManganese sulfate
MagnesiumMagnesium phosphate
NiacinNiacinamide or nicotinic acid
PhosphorusMagnesium phosphate or potassium phosphate
PotassiumPotassium bicarbonate, potassium chloride, potassium citrate, or potassium phosphate
SeleniumSodium selenite
SodiumSodium selenite
Vitamin APalmitate
Vitamin B1Thiamine hydrochloride
Vitamin B2Riboflavin
Vitamin B5Pantothenic acid or calcium pantothenate
Vitamin B6Pyridoxine hydrochloride
Vitamin B12Cyanocobalamin
Vitamin CAscorbic acid or ascorbyl palmitate
Vitamin DCholecalciferol
Vitamin EDL-alpha tocopheryl acetate or mixed tocopherol concentrate
Vitamin KPhytonadione
ZincZinc sulfate

We’ve also listed other common minerals and prebiotics, as well as other ingredients added to formulas. These “extras” are not required by the FDA, but they are all considered safe. Formula companies add these ingredients because they may confer potential benefits or are designed to make the formula more similar to breast milk. And some ingredients act as emulsifiers or thickeners for the formula’s consistency.


What you’ll read on the labelCrypthecodinium cohnii oil or Schizochytrium sp. oil (DHA);
Mortierella alpina oil (ARA)
What it isOmega-3 fatty acids
The evidenceThere has been quite a bit of research done, but the results are mixed—some show benefit, and some show no benefit. It is found in breast milk in variable amounts.


What you’ll read on the labelBeta-carotene
What it isA nutritional antioxidant
The evidenceIt is found in breast milk, but there aren’t studies showing it is beneficial in formula.


What you’ll read on the labelLactoferrin
What it isConsidered an “immune-supporting protein”
The evidenceIn a large study formula with added lactoferrin did not decrease infections or allergies, but the study authors say the research was not designed to detect subtle differences.


What you’ll read on the labelL-carnitine
What it isNutrient involved in energy metabolism
The evidenceL-carnitine is made by our bodies, but newborns can be deficient. It is naturally found in cow’s milk–based formulas, but it is present in higher levels in breast milk so many formulas have added it.


What you’ll read on the labelLutein
What it isA nutritional antioxidant that appears to be involved in brain and eye development
The evidenceIt is found in breast milk, but there are no studies showing that it is beneficial in formula.


What you’ll read on the labelLycopene
What it isA nutritional antioxidant
The evidenceIt is found in breast milk, but there are no studies showing that it is beneficial in formula.

Milk fat globule membrane (MFGM)

What you’ll read on the labelWhey protein-lipid concentrate
What it isA mix of phospholipids, fats, and proteins coating the fats in milk
The evidenceThere is some evidence that MGFM has cognitive benefits and may defend against infections. There are limitations to these studies, including that many of the authors have industry affiliations, and we don’t know if the effects are sustained long-term.


What you'll read on the labelCytidine-5-Monophosphate, Adenosine-5-Monophosphate,
Disodium Uridine-5-Monophosphate,
Disodium Guanosine-5-Monophosphate,
Disodium Inosine-5-Monophosphate
What it isMakes DNA and RNA (building blocks of our genetic material)
The evidenceSeveral studies have linked nucleotides in formula to increased levels of certain polyunsaturated fatty acids in infant blood (these fatty acids are thought to have benefits for the brain, but the link between nucleotides in formula and brain development has not been established). One study showed increased weight gain and head growth for infants fed formula with nucleotides, compared with those fed a formula without nucleotides.


What you’ll read on the label2’-Fucosyllactose (2’-FL), fructooligosaccharides,
galactooligosaccharides, polydextrose
What it isThese are sugars that feed gut microbes, they are the third most abundant component of breast milk, and in breast milk there are around 200 different kinds.
The evidenceFructooligosaccharides, galactooligosaccharides, and polydextrose are structurally different from the gut-feeding sugars found in breast milk, and a review of 41 studies found they had no benefit.


What you’ll read on the labelLactobacillus reuteri or Bifidobacterium lactis
What it isBeneficial bacteria
The evidenceLactobacillus reuteri, a beneficial bacteria found in breast milk, has been shown to reduce colic-related gas in breast-fed babies, but adding it or other bacteria strains to formula has shown limited to no benefit in a number of studies.


What you'll read on the labelTaurine
What it isThe most abundant free amino acid in breast milk, it helps absorb fat, helps the liver deal with waste, and appears to help in brain development.
The evidenceStudies have not shown a benefit to adding taurine to formula in the short term (and long-term benefits have not been studied).

Non-nutritive ingredients

What you’ll read on the labelSoy lecithin, sodium citrate, monoglycerides, potassium
What it isThese ingredients act as emulsifiers (help keep oils from separating), thickeners, stabilizers (prolong shelf life), and/or provide pH control.
The evidenceAll ingredients in formula are proven to be safe.

What’s in baby formula?

The infant formulas we recommend.

Baby formula in the US is based on either non-fat cow’s milk or soy. Porto and Thomas told us they recommend soy-based formulas only if the baby has a medical need for it, or if parents want their baby to follow a vegan diet; this is also the guidance from the American Academy of Pediatrics. For this guide, we looked only at cow’s milk–based formulas.

Lactose is the carbohydrate occurring naturally in breast milk and cow’s milk, and it is the most abundant component of breast milk. Some formulas marketed as “sensitive” have reduced lactose or are lactose-free and instead use corn syrup, sucrose, or other sugars. A Pediatrics in Review article states that “primary lactose intolerance is rare in children,” and most healthy babies are able to tolerate lactose, whether from cow’s milk or breast milk. Porto said that when a baby is having issues digesting a formula, it’s usually due to the protein and not the carbohydrate. Porto and Young both said they prefer babies to be on lactose-based formulas.

Our research showed that each formula brand uses its own standard blend of fats in all of its formulas. Fat is the second-most-abundant component of human breast milk, after carbohydrates. But all US formulas use plant-based fats, the most common being coconut, soy, sunflower, safflower, or palm oil. Young says for some babies, palm oil might contribute to constipation, but “most infants are able to pass stool while consuming palm oil just fine.” Porto said if a formula-fed baby has hard stools, palm oil wouldn’t be the first thing he would consider as a culprit. He would first make sure that the baby was hydrated, and then maybe recommend a formula with hydrolyzed proteins, since, as we note above, some babies have difficulty digesting intact milk proteins. However, if you want a formula that doesn’t use palm oil—some people may also want to avoid it for environmental reasons—Kirkland Signature ProCare, all Similac formulas, and Bobbie formulas don’t include it.

Aside from carbohydrates and fats, cow’s-milk formulas contain different forms of milk proteins:

  • Intact: The cow’s-milk proteins have not been broken down. Baby formulas with intact proteins, often called “traditional” formulas, are the most commonly used. Porto, Thomas, and Young stated that most babies do well on traditional formula.
  • Partially hydrolyzed: The milk proteins have been partly broken down, which makes them closer to the size of the proteins in breast milk. Formulas with this type of protein are often labeled “gentle” or “tender,” and they are marketed as being easier to digest.
  • Extensively hydrolyzed and amino acid: The proteins have been fully broken down into peptides or amino acids. Formulas with extensively hydrolyzed protein are sometimes called “hypoallergenic,” and they’re for babies who are allergic to milk proteins or those who have or are at risk for other medical issues. You should consider these formulas only if your baby has a diagnosed medical need for them.
  • A2: In 2020, Enfamil, Gerber, and Similac released formulas featuring A2 milk. A1 and A2 refer to the type of beta-casein (a protein) found in milk. Human milk contains A2 beta-casein. Most cow’s milk contains predominantly A1 beta-casein. But some cows produce A2 beta-casein, which is used in A2 formulas and is claimed to be more similar to breast milk. “I don’t think we have great data in the United States for the actual benefit [of A2 formula],” Porto said, and he said he’s skeptical that there would be any benefit. However, he acknowledged that for a baby who seems to have a milk-protein sensitivity, A2 milk formula could potentially be easier to digest, in the same way that formulas with broken-down (or hydrolyzed) proteins are.
  • Whey vs. casein: Most formulas add whey protein in addition to casein protein to make the ratio of the milk proteins more similar to human breast milk. Young generally advises first-time formula users (especially those whose babies have not yet started solids) to try a “formula that at least has some extra whey added. That’s because breast milk itself is whey predominant.” Human breast milk settles into a ratio that’s about 60% whey and 40% casein—though in the first few weeks after birth, human milk can be up to 90% whey. Some formulas use whey protein exclusively without any casein protein.

For this guide, we considered only intact (traditional), intact organic, and partially hydrolyzed (sometimes called “tender” or “gentle”) formulas.

Closeup of the ingredient list of a formula we recommend.

Finally, in addition to the FDA-mandated 29 vitamins and nutrients that all infant formulas must include, we found that many formulas have added nutrients and ingredients (what we call “extras”), which are intended to make formulas more similar to—or to confer benefits associated with—breast milk. All of the formulas we found have some of these “extras”; none have all of them. Here are details on some of the main “extras” you’ll find in baby formula (see the chart above for a full list):

  • DHA and ARA are fatty acids present in breast milk. Research suggests that DHA promotes brain and eye development, and that ARA plays a role in reducing inflammation. However, a systematic review of studies on DHA and ARA in formula have not shown conclusive benefits. Though DHA and ARA are not mandated by the FDA, almost all formulas now contain them. Young and Porto both said it’s worth feeding babies formula that includes these fatty acids for the potential benefits.
  • Milk fat globule membrane (MFGM) is a mix of phospholipids, fats, and proteins naturally coating the fats in breast milk. MFGM is found in cow’s milk, too, but it’s removed in the process of making formula. Now some companies are adding it back. In one study, funded by a baby food company, a group of babies under 2 months old were exclusively fed a formula that included MFGM until they were 6 months old. Those babies did have slightly higher scores in a measure of cognition at 12 months, compared with babies fed formula not containing MFGM. But, Porto said, “we don’t know if those effects are sustained.” (There are also other limitations to that study.)
  • Human breast milk has over 200 kinds of prebiotics, or oligosaccharides (sugar molecules), that feed a baby’s gut microbes, and these prebiotics are the third-most-abundant component of breast milk, after carbohydrates and fats. Prebiotics are considered a promising area of breast-milk and formula research and development. And breast-milk researcher Lars Bode told us that the unique prebiotic components in breast milk positively affect the baby’s gut microbiome and immune system, prevent infection, and have other benefits. Most manufacturers now include at least one prebiotic, either in the form of a human milk oligosaccharide (HMO) called 2’-Fucosyllactose (2’-FL) or in fiber-based forms called fructooligosaccharides or galactooligosaccharides. There is little evidence that prebiotics added to formula are helpful. Breast-milk researcher Bode and pediatricians Anthony Porto and Jenny Thomas all cautioned that the few prebiotics currently added to formula haven’t been proven to affect a baby’s gut microflora and immune system the same way the many dozens of unique prebiotics found in breast milk do.
  • Probiotics are included in some formulas, or you can add your own when mixing formula (Gerber, Enfamil, and others sell infant probiotics). Porto cautioned to add probiotics only after consulting your child’s pediatrician. The beneficial bacteria found in breast milk, Lactobacillus reuteri, has been shown to reduce colic-related gas in breastfed babies. But one study did not find the same effect when babies were fed formula that included the bacteria, and separate studies found limited benefits to using other bacterias. Porto said that one of the best things you can do for a baby’s gut flora is “limiting the use of antibiotics, especially during the first few years of life.”

Though these additives are all recognized as being safe by the FDA, a 2017 article on infant nutrition in Pediatrics in Review concluded: “The benefits of these additives are still under investigation.” Research into breast milk is ongoing. And the makeup, role, and benefits of many of of breast milk’s bioactive components, like white blood cells, immunological proteins, beneficial microbes (probiotics), and prebiotics, among many others, are still being understood.

“We have come ages in formula development. But [formula makers] are nowhere close to creating human milk,” Thomas said. “I don’t think that any of the newest additions to formula makes any one formula so great that you should stand up and say this is the one that you need.”

Many formulas have added ingredients that are meant to confer benefits associated with breast milk, but the effectiveness of these additives is still under investigation.

Following the guidance of these experts and other medical sources, we considered these formula “extras” to be just that: safe to consume, maybe nice to have, but not yet conclusively beneficial. These ingredients are one of the reasons the cost of formulas can vary so widely, but Young said you don’t need to stretch your budget for them. And when it comes to formula companies touting certain ingredients as improving babies’ development or cognition, Young tells parents to be skeptical. Instead, she said: “Talk to your baby, make eye contact with your baby, snuggle with your baby, read to your child—all of those things together make such a bigger impact that there’s just no room for parents to feel any guilt if a formula is out of their financial reach.”

How we picked

The infant formulas we recommend.

We started our research in 2017 by building a list of all infant formulas made by the four major US companies that make formula: Mead Johnson (Enfamil); Abbott Nutrition (Similac); Nestlé (Gerber); and Perrigo (which makes generic formulas). Each of these companies makes a half-dozen or more types of formula, and in 2017, we ended up with a list of over 50 formulas. For a 2021 update of this guide, we reanalyzed the formulas (some had been discontinued), and we scrutinized the compositions and ingredients of eight new formulas.

Brand-name and store-name formulas are nearly identical.

We focused on powdered formulas, because they are the most commonly used (PDF) and most economical, and they come in the most varieties. Enfamil, Similac, and Gerber offer some of their formulas in liquid concentrate (which must be diluted) and ready-to-feed versions. Ready-to-feed formulas, some of which come in 2-ounce or 8-ounce pre-portioned bottles, are the most convenient and foolproof option because they require no mixing or dilution. They are significantly more expensive than powdered formulas, though. Based on our extensive research and conversations with multiple experts, there were only a few criteria we used to narrow our list of contenders for best formulas:

Traditional and organic formulas should have lactose as the sole carbohydrate. Since lactose is the energy-providing carbohydrate naturally found in breast milk and cow’s milk, and because formula seeks to mimic breast milk as closely as possible, Porto and Young said it’s preferable to choose a formula that has lactose as the sole sugar. Most healthy babies don’t have issues digesting lactose, and there is little evidence that reduced lactose or lactose-free formulas reduce colic. For this reason, we didn’t consider any “sensitive” formulas that were lactose-free. (All partially hydrolyzed formulas include another sweetener in addition to lactose, so this criterion doesn’t apply to them.)

Many cheaper formulas have most or all of the same extra nutrients as more expensive formulas.

“Gentle,” or “tender,” formulas should contain only partially hydrolyzed proteins. If your pediatrician believes your baby would benefit from a “gentle” formula (which may be easier to digest), it should not contain “intact” proteins along with the partially hydrolyzed ones. (If the label lists milk in addition to hydrolyzed milk or hydrolyzed whey, then it contains both intact and partially hydrolyzed proteins.) This is because, according to Young (video), the presence of some intact proteins will negate any benefits the partially broken down proteins could offer. (Imagine you’re lactose-intolerant and you order an almond-milk latte but still put whipped cream on top.)

Finally, we considered cost. Formulas can range from just under 50¢ to nearly $2 per ounce of powder or more; this translates to about 45¢ to $1.75 per 6-ounce bottle. We found that many cheaper formulas had most or all of the same extra nutrients as more expensive formulas. We did not look at European formulas like HiPP and Holle because they are some of the most expensive options, aren’t regulated by the FDA, and aren’t sold in US stores. Because European formulas are not FDA-regulated, and shipping them abroad carries risks, experts recommend against using them in the US. (If you want to learn more about why some parents are drawn to European formulas, read our article on this topic.) We also did not consider formulas intended for babies who are premature or who have other medical conditions, including formulas whose proteins are extensively hydrolyzed or come in the form of amino acids (such as Abbott’s EleCare, Enfamil PurAmino, Similac Alimentum, or Enfamil Nutramigen).

We didn’t do any testing for this guide, because babies have minds of their own, and it would be impossible to control for all of the variables that might make a baby prefer one formula over another.

Our pick: Kirkland Signature ProCare Non-GMO Infant Formula

Kirkland Signature ProCare formula

At about 50¢ per ounce (for a pack of four 42-ounce containers), Kirkland Signature ProCare Non-GMO Infant Formula is among the least expensive traditional formulas we found. Yet it is just as safe and nutritious as formulas that cost much more. It uses lactose as the sole carbohydrate, and it has added whey protein to make the protein ratio more similar to breast milk (close to 50% whey and 50% casein). It also includes the extra nutrients DHA and ARA, lutein, taurine, L-carnitine, nucleotides, and two prebiotics (fructooligosaccharides and 2’-FL). This formula uses safflower oil, rather than palm oil, which may be a benefit if you are concerned about constipation (though our experts said palm oil is unlikely to impact a baby’s stool).

Closeup of the ingredient list of the Kirkland Signature ProCare formula

Kirkland Signature ProCare Non-GMO Infant Formula is a generic formula available only at Costco. The Costco representative we corresponded with said its policy is to not disclose the company that manufactures its formula, but Perrigo Nutrition lists the Kirkland formula on its website. Kirkland Signature ProCare Non-GMO has a similar ingredients list to the name-brand Similac Pro-Advance, which costs more than $1 per ounce.

We previously recommended Kirkland Signature Non-GMO, which Costco discontinued in late 2019 and replaced with Kirkland Signature ProCare Non-GMO. The old and new versions of Kirkland’s formula are virtually identical, with minor differences in the amounts and concentrations of certain ingredients.

Flaws but not dealbreakers

Some customer reviewers have complained that their babies experienced gassiness or spit-up when switching from the previous version of this formula, Kirkland Signature Non-GMO, to the new version, Kirkland Signature ProCare Non-GMO. As noted above, most babies tolerate switching formulas well, and the ingredients in the old and new versions differ very little. Some reviewers have also complained that the ProCare formula comes with an opaque blue scoop, which makes it harder to gauge the measurement. This formula is available online only as a pack of four 42-ounce containers, enough for about 136 8-ounce bottles. If you want to buy smaller quantities of formula at a time, you can purchase individual Kirkland formula 42-ounce cans in-store, or try Member’s Mark Infant (which comes in a single 48-ounce container, enough for about 38 8-ounce bottles) or Up & Up Advantage (which comes in a single 35-ounce container, enough for about 28 8-ounce bottles). Though you don’t have to be a Costco member to buy this formula online, non-members pay a 5% surcharge. But even with that charge, this formula remains significantly less expensive than similar formulas from Similac and Enfamil.

Our pick: Member’s Mark Infant

Member’s Mark Infant

Like Kirkland Signature ProCare, Member’s Mark Infant is produced by Perrigo Nutrition. Its ingredients list is largely the same as that of Kirkland Signature ProCare, with added whey, and lactose as the sole carbohydrate (making this formula’s protein close to 60% whey and 40% casein). ProCare contains both galactooligosaccharides and fructooligosaccharides as prebiotics, and DHA and ARA. It also uses safflower oil, rather than palm oil.

Member’s Mark Infant ingredient list

At about 44¢ an ounce (if you’re a Sam’s Club member; if not, you’ll pay a 10% upcharge), this formula is barely a third the cost of name-brand formulas, like Enfamil Premium Infant (which has a similar ingredients list). Member’s Mark comes in a smaller quantity than Kirkland Signature ProCare (one 48-ounce container, versus Kirkland’s four 42-ounce containers). Member’s Mark Infant is sold at Sam’s Club, and the exact same formula is also sold under other brands, including Up & Up Infant at Target, Parent’s Choice Premium Infant at Walmart, Little Journey Infant at Aldi, and Mama Bear Infant on Amazon (though these versions are often more expensive than the Member’s Mark version).

Flaws but not dealbreakers

Member’s Mark Infant doesn’t include lutein or 2’-FL (a human milk oligosaccharide), which Kirkland Signature ProCare does. (As noted above, the benefits of 2’-FL or other prebiotics currently added to infant formulas aren’t firmly established.) The same formula sold under other names (like Up & Up Infant, Parent’s Choice Premium Infant, and Mama Bear Infant) can be considerably more expensive. However, some of those options are sold in even smaller quantities, and this could allow caregivers to try the formula before buying a full 48 ounces from Sam’s Club.

Also great: Up & Up Advantage Infant Formula

Up & Up Advantage

Though slightly more expensive than Kirkland Signature ProCare and Member’s Mark Infant, Target’s Up & Up Advantage Infant Formula is still one of the least expensive formulas we found, yet it contains many of the same beneficial ingredients as much more expensive formulas. Like Kirkland Signature ProCare (and the name-brand Similac Pro-Advance), Up & Up Advantage uses lactose as the sole carbohydrate, has added whey protein (making the protein in this formula about 50% whey and 50% casein), and includes the extra nutrients DHA and ARA, lutein, taurine, L-carnitine, nucleotides, and two prebiotics (fructooligosaccharides and 2’-FL). Unlike Kirkland’s formula and Sam’s Club’s Member’s Mark formula, Up & Up Advantage does contain palm oil, though it shouldn’t be a problem for the majority of babies.

Up & Up Advantage ingredient list

Like ProCare and Member’s Mark, this formula is manufactured by Perrigo Nutrition; it is also sold as CVS Advantage, Sam’s Club Advantage, Walgreens Advantage, Aldi’s Little Journey Advantage, and Amazon Brand Mama Bear Advantage, among others. Up & Up Advantage (and the equivalent generics) are available in smaller, 12.4-ounce and 23.2-ounce sizes, as well as in a 35-ounce size.

The best “gentle” formula: Parent’s Choice Tender Infant Formula

Parent’s Choice Tender

“Gentle” or “tender” formulas use partially hydrolyzed milk proteins, which are partly broken down and may be easier for some babies to digest. If you or your pediatrician thinks your baby might do well with a partially hydrolyzed formula, we suggest Parent’s Choice Tender Infant Formula, which is also manufactured by Perrigo Nutrition. It’s the cheapest partially hydrolyzed formula we found, costing about two-thirds the price of partially hydrolyzed formulas by Enfamil, Similac, and Gerber. Parent’s Choice Tender uses only partially hydrolyzed milk protein, and it contains no intact proteins, as some formulas labeled “gentle” or “tender” do. (As we note above, our experts advised that if you’re choosing a partially hydrolyzed formula for your baby’s digestion, you should ensure that it doesn’t also include intact proteins, because those larger proteins would negate any benefits the broken-down proteins might have.)

Parent’s Choice Tender ingredient list

Like all partially hydrolyzed formulas currently available in the US, Parent’s Choice Tender has an additional sweetener (maltodextrin). But it’s also one of the few partially hydrolyzed formulas that contain some lactose, which experts recommend. (Parent’s Choice Tender, Gerber Good Start GentlePro, and Enfamil Reguline are the only partially hydrolyzed formulas that contain at least 50% lactose and no intact proteins.) This formula’s protein is 100% whey, with no casein. It also contains several potentially beneficial extra ingredients, including DHA and ARA, taurine, L-carnitine, nucleotides, and a prebiotic (2’-FL).

The best organic formula: Earth’s Best Organic Infant Formula

Earth’s Best Organic Dairy Infant Formula
SouthernASMR Sounds 😊Target Shelf Straightening / Organizing 😊

CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers

A Tipping Point in Clinical Development

A rapidly emerging immunotherapy approach is called adoptive cell transfer (ACT): collecting and using patients' own immune cells to treat their cancer. There are several types of ACT (see the box below, titled "ACT: TILs, TCRs, and CARs"), but, thus far, the one that has advanced the furthest in clinical development is called CAR T-cell therapy.

Until recently, the use of CAR T-cell therapy has been restricted to small clinical trials, largely in patients with advanced blood cancers. But these treatments have nevertheless captured the attention of researchers and the public alike because of the remarkable responses they have produced in some patients—both children and adults—for whom all other treatments had stopped working.

In 2017, two CAR T-cell therapies were approved by the Food and Drug Administration (FDA), one for the treatment of children with acute lymphoblastic leukemia (ALL) and the other for adults with advanced lymphomas. Nevertheless, researchers caution that, in many respects, it’s still early days for CAR T cells and other forms of ACT, including questions about whether they will ever be effective against solid tumors like breast and colorectal cancer.

The different forms of ACT "are still being developed," said Steven Rosenberg, M.D., Ph.D., chief of the Surgery Branch in NCI's Center for Cancer Research (CCR), an immunotherapy pioneer whose lab was the first to report successful cancer treatment with CAR T cells.

But after several decades of painstaking research, the field has reached a tipping point, Dr. Rosenberg continued. In just the last few years, progress with CAR T cells and other ACT approaches has greatly accelerated, with researchers developing a better understanding of how these therapies work in patients and translating that knowledge into improvements in how they are developed and tested.

"In the next few years," he said, "I think we're going to see dramatic progress and push the boundaries of what many people thought was possible with these adoptive cell transfer–based treatments."

A "Living Drug"

CAR T cells are the equivalent of "giving patients a living drug," explained Renier J. Brentjens, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center in New York, another early leader in the CAR T-cell field.

As its name implies, the backbone of CAR T-cell therapy is T cells, which are often called the workhorses of the immune system because of their critical role in orchestrating the immune response and killing cells infected by pathogens. The therapy requires drawing blood from patients and separating out the T cells. Next, using a disarmed virus, the T cells are genetically engineered to produce receptors on their surface called chimeric antigen receptors, or CARs.

These receptors are "synthetic molecules, they don't exist naturally," explained Carl June, M.D., of the University of Pennsylvania Abramson Cancer Center, during a recent presentation on CAR T cells at the National Institutes of Health campus. Dr. June has led a series of CAR T cell clinical trials, largely in patients with leukemia.

These special receptors allow the T cells to recognize and attach to a specific protein, or antigen, on tumor cells. The CAR T cell therapies furthest along in development target an antigen found on B cells called CD19 (see the box below, titled "The Making of a CAR T Cell").

Once the collected T cells have been engineered to express the antigen-specific CAR, they are "expanded" in the laboratory into the hundreds of millions.

The final step is the infusion of the CAR T cells into the patient (which is preceded by a "lymphodepleting" chemotherapy regimen). If all goes as planned, the engineered cells further multiply in the patient's body and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces.

The Making of a CAR T Cell

A growing number of CAR T-cell therapies are being developed and tested in clinical studies.

Although there are important differences between these therapies, they all share similar components. The CAR on the cell’s surface is composed of fragments, or domains, of synthetic antibodies. The domains that are used can affect how well the receptor recognizes or binds to the antigen on the tumor cell.

The receptors rely on stimulation signals from inside the cell to do their job. So each CAR T cell has signaling and "co-stimulatory" domains inside the cell that signal the cell from the surface receptor. The different domains that are used can affect the cells' overall function.

Over time, advances in the intracellular engineering of CAR T cells have improved the engineered T cells' ability to produce more T cells after infusion into the patient (expansion) and survive longer in the circulation (persistence).

Advances have also been made in how long it takes to produce a batch of CAR T cells. Although it initially took several weeks, many labs have now reduced the time to less than 7 days.

A Possible Option Where None Had Existed

The initial development of CAR T-cell therapies has focused largely on ALL, the most common cancer in children.

More than 80% of children diagnosed with ALL that arises in B cells—the predominant type of pediatric ALL—will be cured by intensive chemotherapy. But for patients whose cancers return after chemotherapy or a stem cell transplant, the treatment options are "close to none," said Stephan Grupp, M.D., Ph.D., of the Children's Hospital of Philadelphia (CHOP).

Relapsed ALL, in fact, is a leading cause of death from childhood cancer.

Dr. Grupp has led several trials of CAR T cells in children and young adults with ALL that had recurred or was not responding to existing therapies. In one of these earlier trials, which used CD19-targeted CAR T cells, all signs of cancer disappeared (a complete response) in 27 of the 30 patients treated in the study, with many of these patients continuing to show no signs of recurrence long after the treatment.

These early successes laid the foundation for a larger trial of a CD19-targeted CAR T-cell therapy, called tisagenlecleucel (Kymriah™), for children and adolescents with ALL. Many of the patients who participated in the trial, funded by Novartis, had complete and long-lasting remissions. Based on the trial results, FDA approved tisagenlecleucel in August 2017.

Similar results have been seen in trials of CD19-targeted CAR T cells led by researchers in CCR's Pediatric Oncology Branch (POB).

The progress made with CAR T-cell therapy in children with ALL "has been fantastic," said Terry Fry, M.D., a lead investigator on several POB trials of CAR T cells who is now at Children's Hospital Colorado. CD19-targeted CAR T cells were initially tested in adults. But the fact that the first approval is for a therapy for children and adolescents with ALL is a watershed moment, Dr. Fry continued.

The agency approving a new therapy in children before adults "is almost unheard of in cancer," he said.

However, there is no shortage of promising data on CAR T cells used to treat adult patients with blood cancers. CD19-targeted CAR T cells have produced strong results not only in patients with ALL but also in patients with lymphomas. For example, in a small NCI-led trial of CAR T cells primarily in patients with advanced diffuse large B-cell lymphoma, more than half had complete responses to the treatment.

"Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas, who, until this point, were virtually untreatable," said the trial's lead investigator, James Kochenderfer, M.D., of the NCI Experimental Transplantation and Immunology Branch.

Since that time, findings from a larger trial funded by Kite Pharmaceuticals (which has a research agreement with NCI to develop ACT-based therapies) have confirmed these earlier results and formed the basis for FDA's approval of Kite's CAR T-cell product, axicabtagene ciloleucel (Yescarta™), for some patients with lymphoma.

The results in lymphoma to date "have been incredibly successful," Dr. Kochenderfer said, "and CAR T cells are almost certain to become a frequently-used therapy for several types of lymphoma."

The rapid advances in and growth of CAR T-cell therapy has exceeded the expectations of even those who were early believers in its potential.

"Did I think it could work? Yes," Dr. Brentjens said. But he initially thought it would be a "boutique therapy" limited to a very small, defined patient group. The experience over the past 5 years, including the entry of the biopharmaceutical industry into the field, has altered his outlook.

"We have cohorts of patients who would have been considered terminal who are now in durable and meaningful remissions with good quality of life for up to 5 years," he continued. "So the enthusiasm for this technology is now quite high."

New Target Antigens for CAR T Cells

Research on CAR T cells is continuing at a swift pace, mostly in patients with blood cancers, but also in patients with solid tumors. As the biopharmaceutical industry has become more involved in the field, for instance, the number of clinical trials testing CAR T cells has expanded dramatically, from just a handful 5 years ago to more than 180 and counting.

Most of the trials conducted to date have used CD19-targeted CAR T cells. But that’s changing quickly, in part out of necessity.

Some patients with ALL, for example, don't respond to the CD19-targeted therapy. And even in those who experience a complete response, up to a third will see their disease return within a year, Dr. Fry said. Many of these disease recurrences have been linked to ALL cells’ no longer expressing CD19, a phenomenon known as antigen loss.

So, in children and young adults with advanced ALL, researchers in NCI’s POB are testing CAR T cells that target the CD22 protein, which is also often overexpressed by ALL cells. In the first trial of CD22-targeted CAR T cells, most treated patients had complete remissions, including patients whose cancer had progressed after initially having a complete response to CD19-targeted therapy.

Similar to the case with the CD19-targeted CAR T cells, however, relapses after CD22-targeted treatment are not uncommon, Dr. Fry explained.

"There is definitely room to improve from the standpoint of the durability of remissions," he said.

One potential way to improve durability and perhaps at least forestall antigen loss, if not prevent it altogether, is to attack multiple antigens simultaneously. Several research groups, for example, are testing T cells that target both CD19 and CD22 in early-phase clinical trials.

CHOP researchers are also testing a CAR T cell that targets both CD19 and CD123, another antigen commonly found on leukemia cells. Early studies in animal models have suggested that this dual targeting may prevent antigen loss.

Antigen targets for CAR T-cell therapy have been identified in other blood cancers as well, including multiple myeloma.

Dr. Kochenderfer and his colleagues at NCI, as part of the collaboration with Kite, have developed CAR T cells that target the BCMA protein, which is found on nearly all myeloma cells. 

In an early-phase clinical trial of BCMA-targeted CAR T cells in patients with advanced multiple myeloma, more than half of the patients had a complete response to the treatment. Kite has now launched a trial to test the BCMA-targeted T cells in a larger group of patients.

Expanding CAR T Cells to Solid Tumors?

There is some skepticism that CAR T cells will have the same success in solid tumors. Dr. Rosenberg believes that finding suitable antigens to target on solid tumors—which has been a major challenge—may prove to be too difficult in most cases.

"Efforts to identify unique antigens on the surface of solid tumors have largely been unsuccessful," he said.

Researchers estimate that the overwhelming majority of tumor antigens reside inside tumor cells, out of the reach of CARs, which can only bind to antigens on the cell surface.

As a result, as has already been shown in melanoma, Dr. Rosenberg said that he believes other forms of ACT may be better suited for solid tumors.

But that doesn't mean that researchers aren’t trying with CAR T cells.

For example, investigators are conducting trials of CAR T cells that target the protein mesothelin, which is overexpressed on tumor cells in some of the most deadly cancers, including pancreatic and lung cancers, and the protein EGFRvIII, which is present on nearly all tumor cells in patients with the aggressive brain cancer glioblastoma.

Early reports from these trials, however, have not reported the same success that’s been seen with blood cancers.

"As far as targeting antigens on solid tumors the same way we go after CD19, I don't think that's going to work in most cases," Dr. Brentjens acknowledged.

Another key obstacle with solid tumors, he explained, is that components of the microenvironment that surrounds them conspire to blunt the immune response.

So success against solid tumors may require a "super T cell," he said, that has been engineered to overcome the immune-suppressing environment of many advanced solid tumors. Work on a CAR T cell with these properties—an "armored" CAR T cell—is ongoing at Memorial Sloan Kettering, he said.

ACT: TILs, TCRs, and CARs

CAR T cells have garnered the lion's share of the attention when it comes to the cellular therapies that fall under the ACT umbrella. But other forms of ACT have also shown promise in small clinical trials, including in patients with solid tumors.

One approach uses immune cells that have penetrated the environment in and around the tumor, known as tumor-infiltrating lymphocytes (TILs). Researchers at NCI were the first to use TILs to successfully treat patients with advanced cancer—initially in melanoma and later in several other cancers, including cervical cancer. More recently, NCI researchers have developed a technique for identifying TILs that recognize cancer cells with mutations specific to that cancer. In several cases, this approach has led to tumor regressions in patients with advanced colorectal and liver cancer.

The other primary approach to ACT involves engineering patients' T cells to express a specific T-cell receptor (TCR). CARs use portions of synthetic antibodies that can recognize specific antigens only on the surface of cells. TCRs, on the other hand, use naturally occurring receptors that can also recognize antigens that are inside tumor cells. Small pieces of these antigens are shuttled to the cell surface and "presented" to the immune system as part of a collection of proteins called the MHC complex.

To date, TCR T cells have been tested in patients with a variety of solid tumors, showing promise in melanoma and sarcoma.

Evolution of CAR T-Cell Therapies

Other refinements or reconfigurations of CAR T cells are being tested. One approach is the development of CAR T-cell therapies that use immune cells collected not from patients, but from healthy donors. The idea is to create so-called off-the-shelf CAR T-cell therapies that are immediately available for use and don't have to be manufactured for each patient.

The French company Cellectis, in fact, has launched a phase I trial of its off-the-shelf CD19-targeted CAR T-cell product in the United States for patients with advanced acute myeloid leukemia. The company's product—which is made using a gene-editing technology known as TALEN—has already been tested in Europe, including in two infants with ALL who had exhausted all other treatment options. In both cases, the treatment was effective.

Numerous other approaches are under investigation. Researchers, for example, are using nanotechnology to create CAR T cells inside the body, developing CAR T cells with "off switches" as a means of preventing or limiting side effects like CRS, and using the gene-editing technology CRISPR/Cas9 to more precisely engineer the T cells.

But there is still more to do with existing CAR T-cell therapies, Dr. Fry said.

He is particularly enthusiastic about the potential to use CAR T cells earlier in the treatment process for children with ALL, specifically those who are at high risk (based on specific clinical factors) of their disease returning after their initial chemotherapy, which typically is given for approximately 2 and a half years.

In this scenario, he explained, if early indicators suggested that these high-risk patients weren't having an optimal response to chemotherapy, it could be stopped and the patients could be treated with CAR T cells.

For patients who respond well, "they could be spared 2 more years of chemotherapy," Dr. Fry said. "That's amazing to think about."


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