Uncovering the Mechanism of Secondary Malignancies Post-CAR T

Following the FDA's investigation of secondary malignancies in chimeric antigen receptor (CAR) T-cell products and subsequent call for boxed warnings to be included on these products, there is much room for discussion about this therapy and its risks vs rewards. While the majority of clinicians agree that the benefits of CAR T outweigh the risks, one point of contention in the field is how CAR T-cell therapy is associated with secondary malignancies. In an interview with Targeted Oncology^TM, Rahul Banerjee, MD, FACP, physician-researcher at Fred Hutch Cancer Center in Seattle, WA, discusses the potential links between CAR T-cell therapy and secondary T-cell malignancies.

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0:05 | There's 3 things to consider. So I think 1, and the field has really anchored on, is that the CAR T is unmasking the side effects of earlier treatments that put people at risk of cancer. So all patients who are treated for 1 kind of cancer are at elevated risk of developing other kinds of cancer. Some of that is potentially genetics or immune dysregulation, and part of that is treatment. In multiple myeloma and lymphoma, we certainly give treatments that have that known risks. So myeloma I'll focus on, so lenalidomide absolutely has been associated with all sorts of second cancers. And many studies, including studies shown that actually predisposes to more aggressive myeloid malignancies such as found in the CARTITUDE-1 study [NCT03548207] of cilta-cel in myeloma. But transplant, bendamustine can often do it as well. So that's kind of the 1 bucket.

0:53 | The second bucket may be that for patients risk of second cancers, CAR T may accelerate that or somehow expedite or unmask in the process to happen more quickly than before. I can think of a couple of scenarios where this is hard to prove, right? It's something that we have to keep a close eye on. It could be for example, that the, you know, what the FDA is really prioritized and focused in on this. But potentially, these cells were already destined to become cancerous, these T cells due to preexisting clonal hematopoiesis or other complications, you put a CAR in them, and that makes them grow faster, faster, faster, and all of a sudden a T cell lymphoma that may have taken 5 years to develop, now it takes 2 years to develop, something like that.

1:31 | And the third possibility, this is what we think is very unlikely, is the mutagenesis, meaning that physically, as you know, for CAR T cells, you are putting a actual molecule with typically the virus into the actual T cell and potentially inserting into a bad spot and directly turning that totally normal cell into a totally cancerous cell. That was the big problem with our early gene therapies back in the early 2000s. We've come a long way since then on multiple fronts. I think all of us believe that that is very unlikely. And it's worth noting that even if you catch someone, this is what the FDA really kind of dived in, on and in the case report from the last [American Society of Hematology Annual Meeting]. But someone who had gotten CAR T for myeloma got secondary T cell lymphoma, they could see the CAR molecule on the T cell ,on the lymphomatous T cells. It doesn't mean the CAR causes the cancer again, bucket number 2, or possibly these T cells are already destined to become cancerous, which we think was true in that case, became unmasked, started growing even faster as a result of the CAR, and seeing the cognate antigen making them grow, grow grow anyways, was the problem.

2:31 | So I think on that scale of 3 possibility that number 3, again, that CAR T cells cause cancer. No one's saying that, the FDA is not saying that, you know, industry is not saying that, academia is not saying that. So I don't think that's very likely at all. And certainly the studies we've seen do not support that. Number 2 and number 1, we're trying to really piece together that is it that the CAR T cells just allow people to live longer and stay in remission for longer such that an otherwise cancer comes out at the same timeline it would have come out and number 2 is something about CAR T cells and how they manipulate, you know, T cell repertoire and immunosurveillance that makes a cancer that was destined to happen happened faster.