Results of two studies presented at the 62nd American Society of Hematology (ASH) Annual, Meeting, and Exposition held virtually from December 5 – 8, 2020, point to new opportunities to reach a broader patient population with chimeric antigen receptor T-cell (CAR T-cell) therapy.

In CAR T-therapy, a patient’s own T cells are genetically modified to express a CAR designed to recognize and bind to a specific target antigen. This allows CAR T-cells to identify and attack target cells. After binding the target antigen, CAR T-cells become activated and release inflammatory cytokines and chemokines, which can lead to the elimination of target cells.

This approach, referred to as cellular immunotherapy, has dramatically improved outcomes for patients with some hematological malignancies. However, this therapeutic approach does not benefit all patients. One new study offers an explanation as to why some patients do not respond to CD19-CAR T-cell therapy. The study’s authors suggest a way to overcome this resistance. Another study suggests CD19-CAR T-cell may be a viable option for some patients with high-risk non-Hodgkin lymphoma who have not responded to standard treatments.

“Getting more data on CD19-CAR T-cell therapy in the high-risk non-Hodgkin lymphoma population is very important,” explained noted Catherine Bollard, MD, of Children’s National Research Institute and George Washington University.

“We know that CD19-CAR T-cell therapy does not work for some patients, so these studies underscore the need to better understand the immune evasion mechanisms T-cells might be susceptible to and not just focus on their role as a vehicle for the CAR. Doing so may improve our capacity to administer effective T-cell immunotherapies.”

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Promise Against Relapsed/Refractory Indolent Non-Hodgkin Lymphoma
Axicabtagene ciloleucel (Yescarta®; Gilead Sciences/Kite Pharma), a cellular immunotherapy, has dramatically improved the outlook for patients with large B cell lymphoma.

When undergoing axicabtagene ciloleucel therapy, a patient’s T-cells are removed and genetically altered to express a receptor that seeks and destroys cancer cells. The engineered cells, called chimeric antigen receptor T-cells, are then re-infused into the patient.

Axicabtagene ciloleucel, also known as axi-cel, uses an anti-CD19 extracellular domain to target and bind to CD19 on the surface of both healthy and malignant B cells. Upon antigen binding, the CD28 costimulatory domain works with the CD3ζ activation domain to enhance the activation and proliferation of CAR T-cells. In turn, this sequence leads to the elimination of CD19-expressing cells.

Favorable safety profile
In a phase II clinical trial, this therapy brought considerable benefits to patients with indolent non-Hodgkin lymphomas, reducing cancer cells to undetectable levels in nearly 80% of study participants. While indolent non-Hodgkin lymphomas are generally slower growing and less aggressive than large B cell lymphoma, the results suggest treatment with axicabtagene ciloleucel may be a promising option for patients who have a history of relapse or a lack of response to available therapies.

Caron Jacobson, MD, MMSc. Medical Director, Immune Effector Cell Therapy Program, Senior Physician and Assistant Professor of Medicine, Harvard Medical School. Photo courtesy: © 2018 – 2020. Dana-Farber Cancer Institute. Used with permission.

“We were very impressed with the magnitude of the responses, and also the durability,” said senior study author Caron A. Jacobson, MD, MMSc, of Dana-Farber Cancer Institute, who will present the study results in an oral presentation on Monday, December 7, at 1:30 p.m. Pacific time during the annual meeting virtual of the 62nd American Society of Hematology.

“This treatment has meaningfully affected high-risk patients with these diseases. I was also struck early on by how favorable the safety profile was compared to what we’ve been seeing in the fast-growing lymphomas such as large B cell lymphoma,” Jacobson added.

In previous trials for large B cell lymphoma, the therapy has been shown to reduce cancer cells below detectable levels, described as a complete response or CR, in a substantial portion of patients.

To test the therapy for treating indolent B-cell non-Hodgkin lymphoma, the researchers administered axicabtagene ciloleucel to 146 patients with either follicular lymphoma or marginal zone lymphoma at multiple U.S. medical centers. Before the trial, the patients all had continuing lymphoma despite undergoing multiple previous treatments.

Researchers tracked patients for a median of nearly 18 months and analyzed efficacy outcomes among the 84 patients with follicular lymphoma who had at least 12 months of follow-up and the 20 patients with marginal zone lymphoma who had at least one month of follow-up. Overall, 92% of participants achieved an objective response to the treatment and 78% achieved a complete response. By 12 months after their infusion, 72% were still in response. After 17.5 months, 64% were still in response.

All 146 treated patients were analyzed for safety. Almost all patients experienced adverse events, with 86% experiencing adverse events of grade 3 or higher. Seven percent experienced grade 3 or higher cytokine release syndrome, and 19% experienced grade 3 or higher neurologic events.

Response rates were slightly higher, and rates of adverse events were slightly lower among patients with follicular lymphoma compared to those with marginal zone lymphoma, trends that Jacobson said may be further illuminated after data become available for a larger number of patients with marginal zone lymphoma.

Personalizing Immunotherapy in Large B Cell Lymphoma
Axicabtagene ciloleucel achieves a complete and lasting response in about 40-50% of patients treated. And while the treatment with axicabtagene ciloleucel has revolutionized treatment for large B cell lymphoma, it does not work for everyone.

In a new study, researchers uncovered a likely explanation for why about one-quarter of patients do not respond well to this therapy. In this study, the researchers used this information to create a modified version of the treatment that may overcome the problem and make the therapy effective for more patients.

In one study, researchers focused on the role of a protein called CD58 in this process. Analyzing genetic samples from 51 patients treated with axicabtagene ciloleucel, the researchers discovered that the tumors of about 25% of the patients lacked a fully functioning version of this protein. In all but one of these patients, the therapy had no lasting effect. The researchers then created a mouse model that lacked CD58 and tested three different CAR T-therapies in the mice.

None worked.

In the next phase of their research, the researchers probed the biological mechanisms further. They determined that CD58 helps activate the engineered T-cells and assists with the process of killing cancer cells.

Without a functional CD58 protein, CAR T-cells are less effective. To overcome this problem, the researchers altered the engineering process by adding another protein, called CD2, to fill the role of CD58.

CD2, the T cell ligand for CD58, plays both an adhesive role and a costimulatory role in T-cells. The researchers noted that CD2 knockout resulted in significantly reduced cytokine production after CAR stimulation. They also observed that re-expression of only the CD2 extracellular domain did not rescue CAR function, confirming that CD2 signaling is essential for full CAR activation.

In additional experiments, the researchers found that modified CAR T-cells are capable of functioning well without CD58 present.

For example, to overcome CD58 loss in large B cell lymphoma, the researchers generated second-and third-generation CAR T-cell constructs integrating CD2 costimulatory domains within the CAR molecule. They observed that while these cis constructs demonstrated increased potency against CD58KO cells in vitro, they were unable to ultimately overcome CD58 loss in vivo. However, the researchers observed that when CARs were co-expressed with an additional CD2 receptor in trans, they mediated significant anti-tumor activity in vivo, overcoming CD58 knockout in tumor cells.

Based on their observations, the researchers believe that their approach, in which they had identified CD58 status as an important biomarker for durable response to CAR T-cells treatment in large B cell lymphoma, could lead to new clinical trials in the next one to two years. If successful, the modified treatment could significantly expand the pool of patients who are most likely benefit from axicabtagene ciloleucel therapy.

Robbie G. Majzner, M.D., Stanford University School of Medicine, Assistant professor, Lucile Packard Children’s Hospital Stanford. Photo courtesy: © 2018 – 2020. Stanford University School of Medicine. used with permission.

“Achieving an uptick of 20-25% in the complete response rate would really bring cures to a large number of additional patients,” observed senior study author Robbie G. Majzner, M.D., of Stanford University School of Medicine, who will present the result of this study in an oral presentation on Monday, December 7, at 7:30 a.m. Pacific time.

“Ultimately, we could potentially screen patients for CD58 status and provide a more precision approach to this therapy,” Majzner added.

In addition to leading to a next-generation therapy for large B cell lymphoma, the work could have relevance for immunotherapy research more broadly.

“CD58 is an emerging biomarker,” Majzner said.

“Endowing immunotherapeutics with the ability to get around CD58 loss may emerge as important for other cancers, as well,” he concluded.

Highlights of prescribing information
Axicabtagene ciloleucel (Yescarta®; Gilead Sciences/Kite Pharma)[Prescribing Information]

Abstracts
[1] Jacobson C, Chavez JC, Sehgal AR, William BM, Munoz J, Salles G, Pashna N. Munshi PN, Casulo C, et al. Primary Analysis of Zuma-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL) (Abstract #700)
[2] CD58 Aberrations Limit Durable Responses to CD19 CAR in Large B Cell Lymphoma Patients Treated with Axicabtagene Ciloleucel but Can be Overcome through Novel CAR Engineering (Abstract 556).

Featured image: Attendees and Speakers during a Scientific Workshop at the American Society of Hematology 60th Annual Meeting at the Orange County Convention Center on, Friday, December 6, 2019. Photo courtesy © 2019 ASH/Matt Herp 2019. Used with permission.

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