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Bespoke or Off-the-Shelf: A CAR-T Conversation With Dr. Yi Lin

December 16, 2021

A CAR-T Conversation

At the 2021 ASH Annual Meeting, in the area of chimeric antigen receptor T-cell (CAR-T) therapies, there were undeniable standout moments, at the Plenary Scientific Session, among the Late-Breaking Abstracts, and throughout the Scientific Program and oral abstracts. From ZUMA-7 to the TRANFORM and BELINDA trials, researchers have been busy investigating CAR-T therapy versus autologous stem-cell transplantation as second-line therapy in relapsed lymphoma. These studies in particular used U.S. Food and Drug Administration (FDA) –approved autologous (bespoke) CAR-Ts including axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel)So, as we close the chapter on another annual meeting and with such a wealth of new knowledge, a question remains: Considering the manufacturing wait times and production failures associated with autologous CAR-Ts, where do off-the-shelf CAR-Ts stand? 

ASH News Daily was fortunate to catch up with Yi Lin, MD, PhD, at the annual meeting to gather her perspectives on off-the-shelf CAR-Ts. Dr. Lin is an associate professor in the Division of Hematology and Experimental Pathology at the Mayo Clinic in Rochester, Minnesota. She is the medical director of the Immune Effector Cell Program and chair of the Cell Therapy Cross-Disciplinary Group at the Mayo Clinic Cancer Center. 


ASH News Daily: Please define for us what is meant by “off-the-shelf” CAR-Ts. And what is the process of manufacturing? Are there pros and cons? 

Dr. Yi Lin: Allogeneic engineered immune effector cells (IECs) have the theoretical advantage of using a healthier source of cells that have not been negatively affected by tumors or prior therapy compared to autologous IECs. A number of cell sources could be used, including cells from healthy donors, cord blood, and induced pluripotent stem cells (iPSCs). While the total dose number generated from a single batch of the allogeneic (allo-) cell source can vary depending on the source, this is generally high and consistent enough to allow for rapid dosing without manufacturing wait time, which can be in the range of a month for current FDA-approved autologous CAR-Ts. Many strategies are being tested to find the optimal balance between reducing the risk of graft-versus-host disease (GVHD) from allo–CAR-T, while still allowing these cells’ expansion and persistence for antitumor effect. Gene editing to delete or disrupt allo–CAR-T’s native T-cell receptor (TCR), such as the TRAC gene, is the most common approach to reduce risk of GVHD.  


AND: What is the current status of off-the-shelf CAR-Ts? 

Dr. Lin:  Both off-the-shelf CAR-Ts and CAR natural killer (NK) cells are being tested in clinical trials. Data from three such clinical trials in lymphoma were presented by oral presentation at this year’s meeting, each using a different technology. ALPHA (abstract 3878, n=49) and ALPHA2 (abstract 649, n=28) generate allo–CAR-Ts from healthy donors, and in addition to the CD19 CAR, use TALEN to disrupt TRAC and CD52. This enables reduction of host rejection of the allo–CAR-T by the addition of CD52 mAb, ALLO-647, to the common lymphodepletion (LD) chemotherapy, fludarabine, and cyclophosphamide. 

PBCAR0191 (abstract 302) uses a proprietary gene editing technology that directly inserts the CD19 CAR into the TCR locus to also then disrupt the native TCR expression. Seventeen patients with lymphoma were presented. 

FT596 (abstract 823) is an allo-NK generated from iPSC also genetically engineered to express CD19 CAR, a non-cleavable CD16, and an IL-15 receptor. Early results from 25 subjects (12 with FT596 alone and 13 with FT596 plus rituximab) were reported.  

As expected, the time from enrollment to cell dosing is within days in these studies, and almost all the enrolled subjects were able to be dosed. This is in comparison to the typical 10 to 20 percent drop-off seen from cell collection to dosing on autologous cell therapy studies. In general, early follow-up across these studies did not identify any GVHD. Cytokine release syndrome and neurotoxicities were mainly grade 1 and 2. Infections, including grade 3 or higher, were high in up to 27 percent of the subjects. Vigilance on types and severity of infections are particularly important given the significant gene editing and immune suppression using an allo- approach.  

Initial responses are encouraging, with complete response (CR) rate in the 40 to 50 percent range across studies. However, the ALPHA/ALPHA2 studies with the longest median follow-up had similar durable CR rates at six months as those seen with autologous CD19 CAR-T, at around mid-30 percent. Notably, in the PBCAR0191 study, it was seen that increasing LD chemotherapy doses significantly increased CAR-T expansion and persistence, which was associated with increased CR rate. Longer follow-up is needed to know the durability of such responses.  

In October 2021, the FDA placed a hold on all Allogene studies pending review of a patient treated on ALPHA2 who developed aplastic anemia after CAR-T infusion and was found to have chromosome abnormality in the CAR-T cells. The patient had partial response in regard to the lymphoma and underwent allo–stem cell transplantation. 


AND: In view of pivotal studies presented at the annual meeting, what lies in the foreseeable future for off-the-shelf CAR-Ts? 

Dr. Lin: The randomized, controlled studies of the FDA-approved CD19 CAR-T versus autologous stem cell transplant in second-line therapy for aggressive lymphoma were definitely among the top discussed presentations for lymphoma this year. In particular, the ZUMA-7 study met its primary endpoint of improved event-free survival with axi-cel (abstract 2). FDA review for the use of axi-cel in second-line therapy is anticipated for April 2022. Additionally, we also heard new data from the ZUMA-12 phase II study where axi-cel was used in the first-line setting for patients with high-risk, aggressive lymphoma, with a 73 percent CR (abstract 739). Given the encouraging results for the use of autologous CAR-Ts in earlier lines of therapy, and the fact that allo–CAR-Ts are still in the early phases of clinical testing, it is likely that allo–CAR-Ts or allo–CAR-NKs with a good safety and efficacy profile will first be positioned in the late line of therapy. Thus, it is encouraging that patients with prior treatment with autologous CAR-Ts have been treated on these allo–CAR-T and allo–CAR-NK studies and clinical responses have been observed. More experience is needed to understand the impact of mechanisms of relapse from autologous CAR-T therapy and thus the likelihood of response to subsequent allo-CAR approaches. Additionally, repeat cell dosing that is beginning to be explored in the current trials appears feasible and can deepen response. 

With all the advances in genetic engineering tools and additional information from ongoing trials, it is conceivable that we can overcome the current limitations seen with allo–CAR-T and test these therapies in the upfront setting in the future. 

Dr. Lin indicated no relevant conflicts of interest. 

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