What the FDA CAR T-Cell Therapy Investigation Means for Oncologists

Drs. John Sweetenham and Fred Locke discuss the FDA investigation on the risk of cancer from CAR T-cell therapy and share insights on the known number of cases and the potential implications on clinical research and patient care. TRANSCRIPT Dr. John Sweetenham: Hello, I’m Dr. John Sweetenham from the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. CAR T-cell therapies have been game changers for treating certain cancers including lymphomas and leukemias, as well as multiple myeloma, since the vast majority of patients who have received CAR-T do not have other curative options with conventional non-cellular, anti-cancer therapies. But on November 28, the U.S. Food and Drug Administration announced that it is investigating whether CAR T-cell therapy can, in rare cases, cause secondary cancers. The FDA launched the probe after receiving reports from clinical trials and other data sources of T-cell malignancies in patients who received CAR T-cell immunotherapies. Joining me to discuss the investigation and its implications for the field is Dr. Fred Locke, a medical oncologist and translational researcher and a senior member and chair in the Department of Blood and Marrow Transplant and Cellular Immunotherapy at the Moffitt Cancer Center in Tampa, Florida. Dr. Locke is an internationally renowned clinical research leader in the field of CAR T-cell therapy. You'll find our disclosures in the transcript of this episode, and disclosures of all guests on podcasts are available at asco.org/DNpod. Fred, it’s great to have you on the podcast today. Dr. Fred Locke: Thanks, John, I’m really glad to be here. Dr. John Sweetenham: So, T-cells are the backbone of CAR T-cell therapies, and there are currently 6 CAR-T products approved by the FDA. As our listeners will know, CAR T-cell therapies manipulate a patient's T-cells, enabling them to recognize and attack antigens on cancer cells and induce potential long-standing changes in the immune system. In its statement on November 28, the FDA said it determined that the risk of T-cell malignancies is applicable to all of the currently approved BCMA- and CD19-directed, genetically modified, autologous CAR T-cell immunotherapies. Fred, could you comment for us on the investigation: How many patients are reported to have developed second malignancies from CAR T-cell therapy, and whether there are likely to be more secondary cancers reported? Dr. Fred Locke: Yes, so the FDA and the reports are coming out that there are 19 cases of T-cell malignancy that we're aware of that have occurred after the current FDA-approved CAR T-cell therapies were administered for the treatment of leukemia, lymphoma, or multiple myeloma. The majority of those cases were reported through the FDA Adverse Event Reporting System. And we don't know a lot of details of those 19 cases. We think that there's probably about 13,000 to 14,000 patients who've been treated with the commercial CAR T-cell therapies. So if you kind of do some crude math, you can come up with 19 out of say, 13,500; we're at about 0.1% of patients who could have developed T-cell lymphoma after treatment with these CAR T-cell therapies. It's not entirely out of the realm of possibility that T-cell lymphoma could develop from gene-modified T-cells, and these are all the patient's own T-cells that have been modified outside of the body. But I would still posit that this is a really low incidence of T-cell lymphomas in these patients who really are without other great treatment options. Dr. John Sweetenham: Yeah, and I think that's a point that we'll return to a little bit later on in the conversation around the fact that you know, clearly, there are major benefits that have been associated with CAR T-cell therapy and hematologic malignancies so far. And of course over the years, I think that many of us have become familiar with and learned a great deal about how to manage some of the more serious side effects of CAR T-cell therapy. And you, of course, have led several pivotal national trials of anti-CD19 CAR-Ts for lymphoma. Can you comment at all on whether you've seen previous data from your own practice or others on the risk of second malignancy from CAR T-cell therapy? And can you share your insights on the data and any new emerging data that warrants our attention for the concern or risk of second malignancy? And I guess to round up that series of questions, is there anything currently in yours or others research into CAR-T to explain what's happening and why this is going on? Dr. Fred Locke: I think what may have prompted the FDA’s announcement of this is that on the same date that they came out with announcing their investigation, there was the release of the abstracts for the American Society of Hematology Annual Meeting. And within those abstracts, and unfortunately it was not selected for poster or oral abstract presentation, but discovered within those abstracts was one on a CAR+ T-cell lymphoma after ciltacabtagene autoleucel therapy for relapsed refractory multiple myeloma. And what these investigators and the company were reporting is that a patient with refractory multiple myeloma received the cilta-cel BCMA-directed CAR T-cell therapy and developed a stringent complete response, and about 5 months later developed a nasal facial plaque and PET+ cervical lymph nodes. And both the lymph nodes and the plaque were biopsied and showed a T-cell lymphoma in which 90% to 100% of the cells were positive by qPCR for the CAR construct and immunohistochemistry for the CAR protein. So this was a T-cell lymphoma growth where the cells were expressing the inserted protein, the chimeric antigen receptor protein, which is obviously not natural. And when they looked a little bit deeper at these patients, 91% of the cells have the same T-cell receptor sequence. So this was really a clonal sort of process. They did CAR integration analysis to see how the insertion of the CAR, the chimeric antigen receptor gene, could have potentially disrupted a gene within the T-cells. And what they found is that there were some dominant sort of insertions within certain genes suggesting monoclonality, but it wasn't within any sort of obvious activating genes that would be expected to lead to the T-cell lymphoma. They went on and did some additional analysis, and they showed that there was some existing TET2 mutations in the T-cells of this patient, prior to probably prior to the CAR T-cell manufacturer, and they weren't associated with clonal insertion. And I think, you know, it's possible that this patient who had a pre-existing mutation may have been susceptible to the development of a T-cell lymphoma prior to the CAR T-cell treatment. And TET2 was previously shown a number of years ago in a CLL patient treated with CD19 CAR T-cell therapy; it was shown that there was insertional mutagenesis, silencing the TET2 gene, and that associated with clonal expansion of the CAR T-cells in that patient and corresponded with remission of the CLL. However, the difference here is that that patient's T-cell clone went back down and contracted, and the patient remained in remission 5 years later with their T-cells still in the blood, but the minority of those T-cells had that that TET2 mutational insertional mutagenesis. All this is something we thought was theoretically possible, that T-cell lymphoma could develop after car T-cell therapy. And in fact, a prior trial using a different method of delivery of a CAR gene; instead of using a virus to insert the car into the into the T-cells, a transposon system called piggyBac was used. And in that trial, again, CD19 CAR trial, but in this case, it was allogeneic donor cells for patients who had relapsed after an allogeneic transplant. So it's sort of an autologous, you know, analogy, but it's using the donor cells. And in that trial, 2 out of like 10 patients developed clonal T-cell lymphoma, which was CAR+, but they weren't able to identify a clear insertional mutagenesis event in those cases. So, we've known this is possible, and it would have been great if this poster or if this abstract at ASH was presented as an oral or a poster so we could get more detail, but it's possible that that's the likely reason for the FDA’s announcement. Dr. John Sweetenham: Thanks. The bottom line, I guess, is that for now, the jury's still out on exactly what's underlying these observations, but something which I'm sure is going to be the subject of a lot of discussion during the ASH meeting this year and moving forward. I'd like to inform our listeners that ASCO released a statement on the FDA investigation, stating that the risk of T-cell malignancies due to CAR T-cell therapy appears to be very low. And we've just heard from Dr. Locke that, of the several thousand patients who've received CAR Ts, there are 19 cases so far, it's been reported, which puts us into some type of proportion. The ASCO statement goes on to say that based on available data, and while such malignancies have occurred in patients who have received CAR T-cell therapy, the causal relationship, whether these cases are spontaneous or are caused by the therapy, needs to be investigated further, and we've just heard a little about the detail of that. ASCO added that by issuing a warning but not revoking approval of these therapies, the FDA clearly believes that the current available evidence suggests the overall benefits of these products, used within their approved label, continue to outweigh the potential risks. So Fred, the risk of secondary malignancies is already included as a class warning in the U.S. prescribing information for these CAR T-cell therapies. But do you think that the CAR-T products could eventually be taken off the market, and how would your research be impacted if this were to happen? And maybe finally, how long will patients on CAR T-cell therapy need to be monitored moving forward? Dr. Fred Locke: I don't believe that CAR T-cell therapy will be taken off the market. As we've already talked about, the incidence is extraordinarily low and the causality is unclear. It would certainly impact my research, as I'm doing clinical trials with CAR T-cell therapies, but it would more importantly impact the way we treat patients. We did over 300 CAR T-cell therapy treatments last year here at Moffitt Cancer Center. We're one of the busiest programs in the world giving CAR T-cell therapy, and it is truly a transformative therapy for all the diseases that we administer these FDA-approved therapies for. For example, in diffuse large B-cell lymphoma, we participated in the ZUMA-7 clinical trial and recently reported that patients randomized to CAR T-cell therapy had improved overall survival. They were living longer than patients randomized in the second-line setting to get conventional chemotherapy and autologous transplant. This is clearly a therapy that can work. I would also add that the risk of secondary malignancies is real, but that's a risk for all cancer patients, particularly patients with hematologic malignancies, and for example, lymphoma patients who've gotten an autologous stem cell transplant are at a relatively high lifetime risk of developing a secondary myeloid malignancy, most commonly, treatment-related MDS or AML. And that risk is also present after CAR T-cell therapy. The degree of attribution of CAR-T versus the condition of chemotherapy for CAR-T versus the previous chemotherapy is all unclear, and more analysis needs to be done. But the risk of developing treatment-related MDS or leukemia is certainly higher than the small number of T-cell lymphomas reported. The other thing I want to point out is that there was an analysis of the SEER database that patients with B-cell lymphomas are at about a 5-fold higher risk of developing a T-cell lymphoma than the otherwise healthy population; and vice versa, by the way, T-cell lymphoma patients are at risk for developing B cell lymphoma. And in fact, in that SEER database, it's not a wildly different percentage chance of developing a T-cell lymphoma after a B-cell lymphoma. And this data came out before the advent of CAR T-cell therapy. So I really think we need more science to be done to understand what's happening for these patients. Will this impact the field? Well, certainly, there are treatments that are not CAR T-cell therapy that compete with CAR T-cell therapy or could; I'm a strong believer that they don't offer the same outcomes for patients, but we will certainly see people talking about this for some time. Then the other place where this could be relevant, I think, is as we look at CAR T-cell therapy for autoimmune disorders, and we're starting to see studies of that for lupus and other diseases, the risk to benefit ratio could be different in those cases. So this is something we really need to consider as we move forward with CAR T- cell therapy. Dr. John Sweetenham: Yeah, thanks, Fred. And as a major clinical investigator in the field of CAR-T at the moment, do you see any potential concerns about difficulties in getting patients onto the trials of CAR T-cell in the light of this information? Dr. Fred Locke: No, I really don't. We're not seeing hesitancy, at least in the patients who are referred in for CAR T-cell therapy. Again, it may give ammunition for those who are already predisposed to not refer patients in for CAR T-cell therapy, but I don't think it should. I think that these are low risks, and these therapies clearly have benefits to patients. And we should give their patients an opportunity to get these therapies, and I don't see it impacting our clinical trials at this point. Dr. John Sweetenham: Yeah, and your comments address what was going to be my final question to you and that is, as a referring oncologist, how would you advise a referring oncologist to talk with their patients about these data and their implications moving forward? Dr. Fred Locke: If the patient brings it up, I think the response should be that these are very few cases of very low incidence and very low risk. There are other risks to CAR T-cell therapy that are greater, and really speaking with a cell therapist who administers the treatment is probably the best way to give the patient the option to get CAR T-cell therapy if they want to, knowing all the risks and benefits. So, I would leave it up to the CAR-T treatment center to discuss those risks with the patient.   Dr. John Sweetenham: Well, thanks, Fred, for sharing your insights with us on these concerning developments in CAR T-cell therapy, and I think also for putting them into context in terms of the sort of magnitude of this problem in the context of the overall number of patients who are benefiting from this therapy right now. We truly appreciate your time, and thanks for sharing your thoughts with our listeners. Dr. Fred Locke: Thanks, John, my pleasure. Dr. John Sweetenham: And thank you to our listeners for your time today. If you value the insights you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.    Find out more about today’s speakers:      Dr. John Sweetenham Dr. Fred Locke @DrFredLocke     Follow ASCO on social media:         @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn         Disclosures:        Dr. John Sweetenham:    Consulting or Advisory Role: EMA Wellness     Dr. Fred Locke: Consulting or Advisory Role: Novartis, Celgene, Calibr, Allogene, Gerson Lehrman Group, EcoR1, Amgen, Bluebird Bio, Bristol Myers Squibb, Iovance Biotherapeutics, Legend Biotech, Cowen, Kite (Gilean), Umoja Biopharma, Takeda, Sana Biotechnology, Daiichi Sankyo/UCB Japan, Bristol-Myers Squibb/Celgene, Janssen, A2 Biotherapeutics, Mittenyi Biotec, Caribou Biosciences, Takeda, Umoja Biopharma Research Funding: Kite Pharma, Allogene, Novartis, Bluebird Bio, Bristol-Myers Squibb/Calgene Patients, Royalties, Other Intellectual Property: Double Mutant Survivin Vaccine. US010414810B2 CAR T Cells with Enhanced Metabolic Fitness; Serial Number: 62/939,727 Methods of Enhancing CAR T Cell Therapies. Serial Number: 62/892,292. Evolutionary Dynamics of Non-Hodgkin Lymphoma CAR-T cell therapy.  Serial Number: 62/879,534. Travel, Accommodations, Expenses: Kite Pharma, A2 Biotherapeutics