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Questions Remain With CAR-T's, Checkpoints in Hematologic Malignancies

Chelsea LoCascio
Published: Monday, Nov 13, 2017

We have done trials comparing that with other regimens and ABVD remains the standard. However, a thorn in the side of ABVD and patients taking it has been the drug bleomycin, which causes pulmonary toxicity, especially in patients who are a little bit older with a smoking history. The question is, “Can we eliminate bleomycin and what would be the replacement?” The replacement might be pembrolizumab or another checkpoint inhibitor, so now we've initiated a trial that Dr Winter is leading to use pembrolizumab plus AVD—eliminating the bleomycin. These are novel ideas using some of the basic science observations over the past 10 to 15 years. It's going to be interesting to hear about that.

Finally, staying with the theme of the immune system, Dr Reem Karmali, who is a new assistant professor in our group, spoke about CAR T cells once again—but this time for diffuse large B-cell lymphoma (DLBCL). There are very exciting data that we're seeing at our institution, [which has treated about] 15 patients so far in a clinical trial.

There are waiting lists for this treatment that, at least at our institution, extending out into January or February. We know that in patients with relapsed or refractory DLBCL, the standard of care has been either an autologous stem cell transplant using patients' own cells or an allogeneic stem cell transplant using a donor’s cell. We know that the results are always a little bit better if we use the donor’s. If we use an allogeneic transplant, we are limited by the toxicity. The question that arises here is, “Can we find a way to make our own T cells attack the lymphoma and spare ourselves the risk, consequences, and toxicity of graft-versus-host disease?”

Based on work that started in Israel many years ago, carried on by Dr Carl H. June and many other investigators around the world, we now have the ability to take our own T cells and, using a lentivirus gene, insert it into those T cells and give it back to the patient. These cells are now revitalized, active, killer T cells, which now recognize the lymphoma as a foreign entity. The concept is a good one. We're still working out the details of the toxicity. There are still concerns, but the clinical trials that are ongoing around the country are exciting.

We had 2 recent FDA approvals with CAR T-cell therapy. What are the biggest questions we have right now with these treatments?

There are probably 3 things that are of concern. I'll start with the most important one. Does it work? Are we going to turn around the way we treat DLBCL? Ultimately, once we identify the target, you can theoretically treat almost any malignancy if the target is there. As it always is in cancer research, the [non-Hodgkin] lymphomas and Hodgkin lymphoma tend to be the leaders because we can study the biology a little bit better and we can gain some ground there.

Does it work? Can we replace aggressive chemotherapy, autologous or allogeneic stem cell transplant with CAR T cells? Certainly, the preliminary data suggest that it works in a significant proportion of patients, maybe more than a 50% complete remission rate and maybe around 40% to 50% of responses that are lasting 6 months or longer. This is in a very heavily treated group of patients.

If it does work, is the toxicity manageable? Is it worth it? Is there mortality? We know that in the acute lymphoblastic leukemia (ALL) study in children—one of the early ALL studies, which was closed—there were 4 fatal brain edema deaths that were related to the treatment. There are neurologic toxicity and blood pressure issues that occur as a result of CAR T-cell therapy. We have to learn how to manipulate the cells to make them safer and what kind of pre-infusion or lymphodepleting therapy we should give to balance the rate of growth of the CAR T cells and the suppression of our own immune system. That has got to be worked out.

Then, if we find that it works and it is not too toxic, great. Then, the big question is, “What does it cost?” At the moment, we are hearing that it's going to be somewhere between $400,000 and $600,000, which is probably legitimate in terms of the right number. Whether it's legitimate in terms of the cost I don’t know. How are we going to afford this in our healthcare system? How are payers going to respond? Will the cost eventually go down?

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Online CME Activities
TitleExpiration DateCME Credits
Oncology Briefings™: Overcoming Chronic Iron Overload in Pediatric AML and MDSJun 30, 20181.0
Oncology Briefings™: Updates in Rare Hematology: Advancing Care and Improving Outcomes for Patients with Aplastic AnemiaAug 31, 20181.0
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