Dr. Copelan discusses the use of chimeric antigen receptor (CAR) T-cell therapy in non-Hodgkin lymphoma patients and how these therapies might improve upon the current standard of care.
Click here to read an expert perspective from Brian Till, MD.
Edward A. Copelan, MD, Chair of the Department of Hematologic Oncology and Blood Disorders at the Levine Cancer Institute in Charlotte, North Carolina, discusses the use of chimeric antigen receptor (CAR) T-cell therapy in non-Hodgkin lymphoma (NHL) patients and how these therapies might improve upon the current standard of care.
Q: Both tisagenlecleucel and axicabtagene ciloleucel are approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma. Are there specific patients for whom these therapies are most suited? How do you decide which patients are the best candidates for CAR T-cell therapy?
DR. COPELAN: The first criterion that helps identify appropriate patients for these treatments is that CAR T-cell therapy is confined right now to those patients who have relapsed or refractory disease. These patients are unlikely to respond to standard treatments. We then try to restrict this therapy to patients who can tolerate the potential side effects of CAR T cells. For instance, cytokine release syndrome is a significant side effect of CAR T cells in many patients, and if patients have significant comorbidities, they are less likely to tolerate this treatment and the toxicities.
In addition, these patients can develop cerebral edema and other neurotoxicities that, again, if they have significant comorbidities, are more likely to lead to poor outcomes. So, we try to restrict CAR T cells to patients who we think could tolerate the toxicities of this treatment.
Q: How have the approval and availability of these therapies changed the way you and your colleagues think about treating NHL, in terms of choosing a first line and subsequent lines of therapy, including stem cell transplants?
DR. COPELAN: These therapies are not first-line therapies at this point, and it is important that our current first-line therapies are effective in a substantial proportion of patients. Most patients who have been treated thus far have failed at least two prior lines of therapies. These patients are highly unlikely to have meaningful responses to traditional agents, but a substantial proportion of the patients we’ve treated with CD19-directed CAR T cells have had responses, most of which have been long-lived. Thus, compared with standard therapies in this setting-that is, for relapsed/refractory patients-CAR T cells appear to be so much more effective than other therapies that there is now a study that is assessing their value when given earlier in the course of disease, including in comparison with autologous transplantation.
Q: In your experience, what have been the challenges with these approved CAR T-cell therapies so far? Is access an issue, for example?
DR. COPELAN: Access is a big problem. It is very clear that most patients who would be eligible and could benefit from these drugs and clinical trials are not referred to the institutions that have access to them. Another challenge is the financial ramifications. These treatments are incredibly expensive, even compared with other novel treatments, and often insurers don’t adequately cover them and the expenses associated with their use. So, aside from the toxicities of the drugs, there are other significant problems to overcome.
Q: Could you highlight some of the ongoing NHL clinical trials that could potentially move CAR T cells into earlier or additional lines of therapy?
DR. COPELAN: As I mentioned, the initial studies were for relapsed/refractory patients, and many of these patients relapsed after transplantation or did not qualify for transplantation on the basis of not responding to chemotherapy.[2,3] So, again, these are the patients with poor prognoses. Current ongoing trials and those in development are and will be testing these agents in the second line and comparing them vs autologous transplant. The multicenter trial in relapsed patients that I mentioned previously is comparing standard chemotherapy and transplantation, which is the traditional and standard treatment for NHL, vs CAR T-cell therapy in a large study that requires a lot of patients and likely will take some time to complete. Eventually, it will tell us whether CAR T cells should be introduced earlier in the course of disease.
Q: Lastly, are there additional novel CAR T-cell therapies in clinical trials for NHL, besides tisagenlecleucel and axicabtagene ciloleucel?
DR. COPELAN: Yes, the most intriguing aspect of CAR T cells is that they have only been around clinically for a short while, so clinicians have understandably focused on the CAR T cells that we are currently using. However, there are basic improvements in CAR T cells that are being developed in the lab, and will be studied mainly in single-institution trials, which in my mind will make CAR T-cell therapy much better. For example, one of the obstacles for CAR T-cell patients who relapse is that the tumor can escape recognition by the CAR T cell by loss of expression of the antigen to which the CAR T cells are directed, which is CD19. One important approach has been to develop dual-targeted CARs so that the CAR T cells will be directed not only to CD19, but also to CD22, which is another protein expressed by B-cell malignancies. There are also studies on CD22-directed CAR T cells to see if these are better than the CARs we are making now.[4,5]
In addition, there are basic studies using gene editing to insert the CAR gene uniformly at the T-cell receptor alpha chain constant region as opposed to current random integration, which results in variable expression in which cells with less expression may be less effective, and others with higher expression suffer tonic CAR signaling and exhaustion. Alternatively, exhausted CARs might be rescued by checkpoint inhibition or other approaches. Thus, some of the current problems limiting the effectiveness of CARs could most likely be overcome by basic progress in the lab right now, which then will evolve into studies at individual institutions. We might be a few years away from multi-institution studies, but these advances will almost certainly dramatically improve the effectiveness and toxicities of CAR T cells. I am really most excited about the basic studies in the lab and the small institutional studies right now, which are sure to improve CARs and their application to patients.
Financial Disclosure:Dr. Copelan has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
CAR T-Cell Therapy: Challenges and Promise
Brian Till, MD
Chimeric antigen receptor (CAR) T cells have emerged as a highly effective treatment for patients with relapsed or refractory aggressive B-cell lymphomas and B-cell acute lymphoblastic leukemia. Challenges do remain with respect to toxicity, access, cost, and insurance coverage, as Dr. Copelan pointed out. Additionally, despite the high response rates, resistance to CAR T-cell therapy or relapse after an initial response remain problems for a significant proportion of patients. However, I am optimistic that as our collective experience with CAR T cells accumulates, we will see improvement in these areas.
With respect to safety, as we gain proficiency in managing cytokine release syndrome (CRS), adverse outcomes should keep decreasing. A deeper understanding of the biology of CRS and neurologic toxicity should also lead to more effective and targeted interventions for treating and even preventing these complications. Improved manufacturing techniques may also influence continued advances in safety. For example, administering cell products formulated with a defined ratio of CD4:CD8 cells seems to be associated with lower toxicity rates, without a loss of efficacy, as suggested by preliminary data from the multicenter TRANSCEND study testing lisocabtagene maraleucel.
We may learn that manufacturing techniques enhance treatment efficacy as well. The group at University of Pennsylvania recently showed, for example, that shortening the culture time of CAR T cells to 3 to 5 days led to improved antitumor function in a mouse model. Another approach being investigated to improve efficacy is targeting multiple antigens, which may help to reduce relapse rates by preventing antigen loss escape. In addition to targeting CD19 in combination with CD22, which Dr. Copelan mentioned, at least one trial is exploring dual targeting of CD19 and CD20. In addition, CARs targeting other antigens are being investigated that could potentially be combined in the future. Perhaps the largest gains in efficacy will come from a better understanding of the biology underlying CAR T-cell interactions with the tumor microenvironment, which may point to ways of overcoming tumor resistance in patients refractory to CAR T-cell therapy.
Finally, cost remains an issue. However, some cost-benefit analyses have shown that these treatments can potentially be cost effective, and more such studies are needed. As CAR T-cell therapies become more efficacious, grow potentially cheaper as competition increases, and can prevent the need for many lines of costly salvage therapies, the costs of treatment may prove to be a good investment for healthcare payers. This may be particularly true if ongoing trials show a superiority of CAR T cells over autologous stem cell transplantation as first-line salvage for diffuse large B-cell lymphoma.
Financial Disclosure: Dr. Till has patents with, and receives royalties and research funding from, Mustang Bio.
Dr. Till is Associate Professor of Medicine, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, and Attending Physician, Seattle Cancer Care Alliance, Seattle, Washington.
1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-44.
2. Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of Juliet: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Blood. 2017;130(suppl):abstract 577.
3. Oluwole OO, Bishop MR, Gisselbrecht C, et al. ZUMA-7: A phase 3 randomized trial of axicabtagene ciloleucel (Axi-Cel) versus standard-of-care (SOC) therapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). J Clin Oncol. 2018;36(suppl):abstract TPS7585.
4. Qin H, Nguyen SM, Ramakrishna S, et al. Novel CD19/CD22 bicistronic chimeric antigen receptors outperform single or bivalent cars in eradicating CD19+CD22+, CD19-, and CD22- pre-B leukemia. Blood. 2017;130:abstract 810.
5. Schultz LM, Davis KL, Baggott C, et al. Phase 1 study of CD19/CD22 bispecific chimeric antigen receptor (CAR) therapy in children and young adults with B cell acute lymphoblastic leukemia (ALL). Presented at the 2018 American Society of Hematology Annual Meeting & Exposition; Dec 1-4, 2018; San Diego, CA. Abstract 898.
6. Eyquem J, Mansilla-Soto J, Giavridis T, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection.Nature. 2017;543:113-7.