Secondary Cancers after CAR-T Cell Therapy

[Jm954]

From New England Journal of Medicine dated 24th Jan 2024 (article is for subscribers only)

This brief report states:

The demonstrated efficacy of the current generation of approved CAR-T products comes along with several well-described safety concerns, including risks of cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, various forms of cytopenia, and hypogammaglobulinemia. Better understanding of some of these risks has led to improved outcomes, such as for patients who develop cytokine release syndrome.

All currently approved CAR-T products employ T cells that are produced by using viral transduction to transfer the genetic construct. Given the relatively recent deployment of these therapies, the Food and Drug Administration (FDA) has issued draft guidance recommending that people who receive CAR T cells engineered with integrating vectors be monitored for extended periods for adverse events, including cancers.

Although CAR-T products have to date been associated with fewer cancers than products made with the previous generation of viruses used for gene therapy transduction, the potential for oncogenesis caused by genomic integration or other mechanisms still exists with the current generation of retroviral vectors.

As of December 31, 2023, the FDA had become aware of 22 cases of T-cell cancers that occurred after treatment with CAR-T products. Such cancers have included T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma. Among the 14 cases for which adequate data are currently available, the cancers have manifested within 2 years after administration of CAR T cells (range, 1 to 19 months), with roughly half occurring within the first year after administration. Cases have been reported in conjunction with five of the six available CAR-T products, but the small number of cases and variation in product use preclude conclusions about the strength of an association with any specific product. Some of these cases are still under investigation.

In three cases for which genetic sequencing has been performed to date, the CAR transgene has been detected in the malignant clone, which indicates that the CAR-T product was most likely involved in the development of the T-cell cancer.

With more than 27,000 doses of the six approved products having been administered in the United States, the overall rate of T-cell cancers among people receiving CAR-T therapies appears to be quite low, even if all reported cases are assumed to be related to treatment.

[AussieNeil Partner Administrator]

The coverage from Medpage Today (free subscription required);

CAR-T Investigation: FDA Leaders Detail Decision on Cancer Risk Warning

— Post-treatment cases grow to 22 since products' initial approvals

medpagetoday.com/hematology...

echoes the above, concluding;

"Moving forward, particularly as the use of CAR T cells for indications outside hematology and oncology is considered, new strategies involving targeting insertion of the CAR construct to specific loci might help reduce the risk of cancers due to integration of the CAR construct at oncogenic loci within the genome," they suggested. "Comprehensive tumor-testing strategies might also generate information on the risk for and nature of these cancers and provide additional mechanistic insights."

Finally, they emphasized that the risk of T-cell cancers developing after the use of these products appears to be low, and appropriate labeling can help clinicians have conversations with patients about the benefits and risks associated with treatment options.

Neil

[ava1967ir]

Hi Jm954 ,please check your chat….

[RogerPinner]

Thanks for posting this Jackie. Does it make me feel more positive for deciding against Car T Cell therapy....not really, but it's very useful to know. I don't think it was it was ever mentioned in any of my discussions with the trial team.

Roger

[bennevisplace]

Thanks for an enlightening post Jackie.

I guess this is a risk whenever a viral vector is used to insert the CAR into the T cell genome. In this comprehensive review of allogeneic CAR T trials (from Teheran of all places) sections 4.1.1 and 4.1.2 cover alternative gene editing/ non-editing strategies, some of which would get around the T cell mutagenesis risk. sciencedirect.com/science/a... Presumably these could be applied to autologous too?

[SeymourB in reply to bennevisplace]

bennevisplace -

Thanks! Great link!

I think the biggest drawback to autologous therapy is cost - hundreds of thousands of dollars per infusion. That's what's driving off-the-shelf allogenic therapy.

=seymour=

[steve5441]

How many of these patients that developed secondary cancers had CLL, sorry I must have missed that part. Were these treatments all "off the shelf" versions of CAR-T. I also must have missed this information during my discussions with my car team at Penn Medicine. This is the third post about this topic in the last month, there has to be more positive information out there to repost, 21 out of 27,000 , wow.

[SeymourB in reply to steve5441]

steve5441 -

These are all autologous CAR-T. I don't think there are any allogenic CAR-T's or CAR-NK's yet approved.

The drugs mentioned in the NEJM article, and their approved indications:

Idecabtagene vicleucel (Abecma) - Multiple Myeloma

Lisocabtagene maraleucel (Breyanzi) - Large B-cell Lymphomas (LBCL and DLBCL)

Ciltacabtagene autoleucel (Carvykti) - Multiple Myeloma

Isagenlecleucel (Kymriah) - Follicular Lymphoma

Xicabtagene ciloleucel (Yescarta) - Large B-cell Lymphomas (LBCL and DLBCL)

Brexucabtagene autoleucel (Tecartus) - Acute Lymphoblastic Leukemia (B-ALL) and Mantle Cell Lymphoma (MCL).

Lisocabtagene maraleucel (Breyanzi) is close to FDA approval for CLL. It and other autologous may be available via clinical trials.

I see 3 allogenic CAR-T and CAR-NK in trials, but none at Penn:

classic.clinicaltrials.gov/...

classic.clinicaltrials.gov/...

classic.clinicaltrials.gov/...

There are several others in trial in China only.

=seymour=