FDA warns CAR-T manufacturers to include warnings of possible secondary T-cell malignancies

But are these concerns warranted, especially when other products seem to have been overlooked for possible safety concerns?

Recently the FDA has issued warnings to manufacturers of a rather new form of cancer therapy called CAR-T therapy with concerns that this new therapy may be associated with possible secondary T-cell malignancies.

This news has hit six companies which have approved CAR-T therapies on the market, with the FDA alerting manufacturers that they must place a warning label on their products for these alleged malignancies.

One example of these letters can be seen below, which was sent to Kite Pharma, Inc. who produces TECARTUS. The most pertinent paragraph is the last one, and for those interested a list of all 6 letters can be found on the FDA’s website, although be aware that the body of the letters are the same aside from approval date, manufacturer, and the intended recipient of the letter.

And following these concerns the FDA noted that the following warning labels must be included with these products:

All of these remarks follow comments made by the FDA in November raising concerns over reports of these malignancies in those who have been provided CAR-T therapy:

With the summary made at the time providing the following remarks:

The Food and Drug Administration (FDA) has received reports of T-cell malignancies, including chimeric antigen receptor CAR-positive lymphoma, in patients who received treatment with BCMA- or CD19-directed autologous CAR T cell immunotherapies.  Reports were received from clinical trials and/or postmarketing adverse event (AE) data sources.

FDA has determined that the risk of T-cell malignancies is applicable to all currently approved BCMA-directed and CD19-directed genetically modified autologous CAR T cell immunotherapies.  T-cell malignancies have occurred in patients treated with several products in the class.   Currently approved products in this class (listed alphabetically by trade name) include the following:

Abecma (idecabtagene vicleucel)

Breyanzi (lisocabtagene maraleucel)

Carvykti (ciltacabtagene autoleucel)

Kymriah (tisagenlecleucel)

Tecartus (brexucabtagene autoleucel)

Yescarta (axicabtagene ciloleucel)

Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action.

Now, these warnings have created a large stir-up among mainstream news outlets as well as among scientists, as noted by an article published in Science after these remarks from the FDA:

But before covering some of these concerns it’s worth briefly summarizing what CAR-T therapy is.

CAR-T Therapy Background

CAR-T therapies are a rather new method of fighting cancer and comes after a long list of other cancer therapies.

Because cancer cells are by all accounts like our own cells the targeting of cancer cells has been rather difficult, with early chemotherapy treatments relying on the idea that cancer cells divide far more rapidly than noncancerous cells as a method of killing the cancer.

This led to the development of various nucleoside analogs that are intended to inhibit DNA replication by relying on the faster rate of cancer cell replication to hopefully uptake these drugs at a higher rate as compared to uncancerous cells, resulting in the cancer’s destruction. Unfortunately, this method of treatment didn’t target only cancer cells, but also targeted any cells that undergo rapid division, thus leading to serious side effects such as hair loss, skin issues, brittle nails, and GI dysfunction for recipients of these treatments.

Afterwards cancer therapy moved towards the direction of immunotherapy which included antibodies that can bind to regions on the surface of cancer cells and direct immune responses. This provided a more targeted approach and helped to overcome some issues regarding cancer’s ability to avoid destruction by the immune system.

However, this research still had limitations, especially when it comes to cancers related to B-cells in which there are still challenges in alerting the immune system to target these cancerous cells.

This eventually would lead to the development of CAR-T as a method of targeting several forms of leukemias and lymphomas by way of genetically modifying autologous (i.e. your own T-cells) so that they can target receptors on the surface of B cells and lead them to their death.

In this case, the two main receptors targeted by CAR-T therapies are CD19 and B-cell maturation antigens (BCMA); the former is a critical component of signaling for B cells¹ whereas the latter is involved with survivability/longevity of B cells.²

Many cancerous B cells express at least one of these receptors on their surface, and therefore have made them prime targets for cancer therapy, leading to development of ways to target these receptors and kill off these cells.

Now, this is where the CAR portion of CAR-T comes in, and it stands for Chimeric Antigen Receptor, and is a method in which T-cells can target CD19 and BCMA.

CAR is chimeric in nature; in that it comprises a synthetic receptor with one portion derived from monoclonal antibodies as well as another portion derived from T-cell receptors. Essentially, this chimeric receptor was constructed with the intent of providing both binding capabilities to either CD19 or BCMA while also inducing an intracellular T-cell response to help kill off these cancerous cells.

The conceptualization of this process may be rather difficult (and I certainly am not doing it justice in my explanation), but this chimeric structure is depicted in the following figure³:

From Boyiadzis, et al. Different generations of CAR-T therapies are highlighted above. What’s similar across all generations is the chimeric nature of the receptor, which is comprised of a monoclonal antibody-like domain that exists on the outside of the T-cell and acts as a binding domain for either CD19 or BCMA. The intracellular portion of the receptor contains T-cell activating properties, and helps to elicit T-cell-related death of cancerous cells.

Note here that the blue, extracellular portion of CAR is the antibody-like portion which binds to either CD19 or BCMA while the orange portion is involved with T-cell activation. Additional modifications are being made to CAR which include the addition of domains that may help with stimulation.

Now, CAR cannot operate on its own, but rather relies on a patients own T-cells in order to present CAR and target cancer cells (hence the T portion of CAR-T). Put another way, CAR must be inserted into a patient’s T-cell so that the patient can express CAR, and this is where genetic modification comes in.

Essentially, a patient’s T-cells are isolated and have the gene for CAR inserted into the cells, usually by way of utilizing a lentivirus or retrovirus that can incorporate the CAR gene. The T-cells are then proliferated and eventually added back into the patient where, hypothetically speaking, these CAR-expressing T-cells can kill off the cancer.

The process is outlined below (taken from NCI):

Is there serious concern with T-cell malignancies?

So with the background out of the way we should examine these concerns with a rational approach. What generally appears confusing about these FDA remarks is that they appear rather aggressive given their otherwise lackadaisical approach when it comes to other therapies.

In some ways, the FDA’s remarks have caught a lot of researchers off-guard as there didn’t seem to be a strong basis for these claims, as noted in the Science article from November:

The CAR-T community was taken aback by FDA’s announcement. Although CAR-T therapy comes with documented side effects, T cell cancers have rarely been associated with treatment in the past. “We have not seen any such event in our patients at MSK,” where hundreds have been treated, Sadelain says.

“We are all completely in the dark regarding the basis for the new concern,” adds Crystal Mackall of Stanford University, who like Sadelain is a pioneer in the field.

Researchers say it’s tough to assess these cancer risks because FDA’s announcement was light on the details.

Granted, remarks about the safety and efficacy of any drug should be taken with some degree of skepticism. As of now there doesn’t appear to be any clear explanation for these incidences of T-cell malignancies.

One concern appears to relate to the use of viral vectors in order to help with integration of the CAR gene into patient T-cells, as there appears to be a possibility that the CAR gene integration process may lead to other alterations in the T-cell genome that can result in cancer development.

The growing process of CAR-T cells may also unwillingly include cells predisposed to cancer development. In this case, selection of T-cells from patients may unfortunately select for cells bearing unwanted mutations, which may then propagate substantially as a consequence of the CAR-T growing process.

There is also the issue of radiation therapy which may induce mutations. Radiation and other chemotherapy treatments may be deployed in order to remove some of the CAR-T patient’s immune cells, making room for more of the CAR-T cells while reducing their need to compete for immunogenic signals, thus making the activity of CAR-T cells more pronounced. Patients undergoing CAR-T therapy may also have undergone chemotherapy and other standards of care beforehand, which carry risk of secondary cancers as well. These processes may unfortunately increase the risk of secondary cancers through DNA damage, and is an unfortunate general consequence of cancer therapies.

All of this suggests possible ways in which T-cell malignancies may occur, but it’s important to note that there again doesn’t appear to be a clearly defined relationship between these therapies and these reports of T-cell malignancies. Bear in mind that CAR-T therapy is also usually provided as a last means when other cancer treatments don’t appear effective. Patients also tend to lean older with other comorbidities which can also contribute to the increased risk of cancer.

What’s interesting is that the insertion of the CAR gene provides clinicians with a way to screen for possible cancerous T-cells by assessing for CAR gene positivity as well as expression of CAR through assays. As of now there doesn’t appear to be enough evidence to argue for or against CAR gene and protein expression and its relationship with these malignancies. This doesn’t mean that there is no relationship, but suggests more research should be conducted in order to examine for possible relationships.

Is this fear warranted?

It is part of this Substack to point out egregious issues when it comes to the FDA’s approval process as I have listed with several recent Alzheimer’s immunotherapies, as well as the growing discussion regarding these GLP-1 RAs. That is to say, I’m generally one who encourages more scrutiny of approvals and more robust assessment for adverse events.

But this is also one of the reasons why the current predicament regarding these CAR-T therapies warrants scrutiny. As of now it’s suspected that over 30,000 patients have received CAR-T therapies. On one hand, this number can be considered rather large within the scheme of overall cancer therapies. On the other hand, this number may pale in comparison to the number of people who have received COVID vaccines, Alzheimer’s immunotherapies, and GLP-1 RAs, and yet there doesn’t appear to be as large as a sweeping concern for these other, more widely used medications.

It also doesn’t help that recipients of CAR-T therapies are usually given this option after standard care fails, suggesting that outcomes and risk of secondary cancer may already be relative high among these individuals. It’s also worth noting that the FDA’s warning appears standard for all 6 approved CAR-T therapies, even though several of them utilize different viral vectors, CAR, and are provided for different B-cell malignancies to different demographics.

From NCI

In essence, the FDA’s sweeping warning doesn’t provide any information as to whether certain CAR-T therapies pose a greater increased risk relative to others, or which reported cases of T-cell malignancies are attributed to which CAR-T therapy, making these warnings even more confusing given how ambiguous they seem to appear.

Again, note that the phrasing of the FDA’s letter, which is the same for all 6 manufacturers, makes it out as if there is evidence that each product may be associated with T-cell malignancies, suggesting that there may be evidence of these T-cell malignancies for all 6 products even though no clear evidence has been provided.

All of this adds further criticism towards the FDA’s rulings on safety and efficacy, as it raises serious questions why the FDA has focused so closely on these CAR-T therapies when there are concerns about other products on the market with clear safety issues.

As a caveat, note that the business of CAR-T therapies is rather lucrative, with some treatments costing upwards of nearly half a million dollars, in which case there would be a strong incentive for companies to downplay possible causal roles between CAR-T and these reported T-cell malignancies.

Hopefully the FDA provides clearer evidence for their concerns that makes them more warranted, but this adds to the growing fact that the FDA continues to be inconsistent in the battles they choose and how they gauge the actual safety and efficacy of therapies on the market.

Thus, these cases of T-cell malignancies should be taken seriously, but so should all adverse reactions reported to the FDA.

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1. Wang, K., Wei, G. & Liu, D. CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol 1, 36 (2012). https://doi.org/10.1186/2162-3619-1-36

2. Roex, G., Timmers, M., Wouters, K. et al. Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma. J Hematol Oncol 13, 164 (2020). https://doi.org/10.1186/s13045-020-01001-1

3. Boyiadzis, M. M., Dhodapkar, M. V., Brentjens, R. J., Kochenderfer, J. N., Neelapu, S. S., Maus, M. V., Porter, D. L., Maloney, D. G., Grupp, S. A., Mackall, C. L., June, C. H., & Bishop, M. R. (2018). Chimeric antigen receptor (CAR) T therapies for the treatment of hematologic malignancies: clinical perspective and significance. Journal for immunotherapy of cancer, 6(1), 137. https://doi.org/10.1186/s40425-018-0460-5