Bispecific CAR-T shows early efficacy, ‘exceptional safety’ in advanced B-cell lymphoma
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Four of five patients with relapsed or refractory B-cell lymphoma demonstrated complete response to an investigational anti-CD19/CD20 chimeric antigen receptor T-cell therapy, according to early data from a phase 1 trial.
Results of the study, presented at the virtual American Association for Cancer Research Annual Meeting, also showed no incidence of high-grade toxicities typically associated with CAR T-cell therapy.
Researchers at University of California, Los Angeles developed the gene-edited autologous bispecific CAR T-cell therapy, which targets CD19 and CD20 proteins commonly found on the surface of B-cell malignancies.
The CAR was manufactured at UCLA, with a total processing time of 7 to 14 days, according to Sanaz N. Ghafouri, MD, hematology/oncology fellow at David Geffen School of Medicine at UCLA. The novel CAR construct includes a CD28 transmembrane domain, a 4-1BB costimulatory domain and a CD3 T-cell activation domain and is processed to modify the agent’s naive/memory T-cell population to enhance CAR T-cell performance and function.
“Bispecific CAR-T is designed to overcome the challenge of antigen escape, which is one of two most common mechanisms of relapse after CAR-T — the other being the lack of CAR-T persistence,” Ghafouri told Healio. “By manufacturing our CAR-T product using these naive/memory T cells, we hope it will make our cells more persistent and improve expansion.”
Ghafouri and colleges reported on the first five patients (median age, 58; range, 29-62; 60% men) who received the bispecific CAR T-cell therapy as part of a dose-escalation study for a range of relapsed or refractory B-cell malignancies. The study group included one patient with mantle cell lymphoma, three patients with follicular lymphoma and one patient with primary mediastinal B-cell lymphoma. Patients had a median four lines of previous therapy, with four of five patients receiving bridging therapy before CAR T-cell infusion.
Four patients received a dose of 50 × 106 CAR T cells (cohort 1), whereas the other patient received a dose of 200 × 106 CAR T cells (cohort 2).
Prior to infusion, all patients underwent standard preconditioning lymphodepletion with 30 mg/m2 IV fludarabine and 500 mg/m2 cyclophosphamide.
Safety, as measured by the incidence of treatment-related adverse events and dose-limiting toxicities within 28 days of infusion, served as the primary endpoint of the study. Secondary endpoints included clinical efficacy based on objective response rate, duration of response, PFS, OS and CAR T-cell persistence.
Median follow-up was 13 months.
The analysis showed no dose-limiting toxicities associated with the novel bispecific CAR T-cell therapy.
Moreover, researchers observed no cases of immune effector cell-associated neurotoxicity syndrome (ICANS), one of the more common treatment-related toxicities associated with CAR T-cell therapy. The other common toxicity — cytokine release syndrome (CRS) — occurred among all five patients, but all cases were mild (grade 1) and resolved without the need for further treatment with steroids or tocilizumab (Actemra, Genentech), according to Ghafouri.
“Our bispecific CAR T cells showed an exceptional safety profile,” she told Healio.
The CAR-T’s antitumor activity between infusion and peak expansion, which occurred around day 14, likely has led to lower overall tumor burden and the lower rates of CRS and ICANS seen so far in the study, she said.
“We know that CRS and ICANS are associated with increased tumor burden at the time of CAR-T expansion,” Ghafouri told Healio. “This product is effectively targeting tumors early on, so by the time peak expansion occurs, we are seeing fewer cases of CRS and ICANS.”
Efficacy results showed four patients (80%) had a complete response to therapy and remained in remission as of the data cutoff point. The remaining patient did not respond to therapy and had early CD19/CD20-negative disease progression that resulted in death.
Median duration of response, PFS and OS had not yet been reached. All patients who responded to therapy demonstrated ongoing CAR T-cell persistence and B-cell aplasia as of data cutoff, according to Ghafouri.
“We are very happy with the results thus far, but these are still just early results,” Ghafouri said.
The study will continue to enroll patients to the higher-dose cohort and the researchers hope to diversify the study population to include patients with other B-cell malignancies, including small lymphocytic lymphoma and chronic lymphocytic leukemia.
“In the long term, hopefully, these anti-CD19/CD20 naive/memory CAR T cells will become standard of care,” Ghafouri said. “They have a lot of potential.”
Perspective
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Philip D. Greenberg, MD
Kinetics and peak expansion of T cells expressing a bispecific CAR appear similar to results reported with cells expressing only a CD19-directed CAR.
The toxicity profile for this therapy looks favorable, with no adverse events not previously seen with CD19-directed CAR T cells. However, it should be noted that four of the five patients received the low initial dose for the study.
The lone nonresponder in this study, who experienced disease progression, was found to have a tumor that was negative for CD19 and CD20 expression. This affirms that bispecific strategies can limit the frequency of but not likely fully prevent escape with antigen loss variants.
The clinical results appear promising, with four of five patients achieving a sustained complete response. However, it is still very early, with just two patients in remission beyond 1 year and two patients at 6 months or less since infusion. I look forward to future results as this trial continues to accrue patients.
Perspective
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Saul Priceman, PhD
There are two major challenges to improving durable therapeutic responses of CAR T cells in patients with hematologic malignancies, as well as to generating comparable robust CAR T-cell responses in patients with solid tumors.
One is tumor antigen heterogeneity and the other is the immunosuppressive tumor microenvironment. Both are driven by intrinsic and/or treatment-acquired mechanisms. The former has been seen after CAR T-cell therapy across multiple tumor types — hematologic and solid tumors alike.
Dual- or multitargeted CAR T-cell strategies are being clinically investigated as an opportunity to “box in” tumors and prevent antigen escape. Based on a bispecific CD19/CD20 CAR T-cell technology developed in the lab of Yvonne Y. Chen, PhD, the team at UCLA provided early therapeutic readouts of five treated patients with lymphoma.
The response rate is very encouraging, and results thus far support the clinical safety of this approach. Although additional patients and long-term follow-up are needed to truly appreciate the overall impact of bispecific CAR T cells for treatment of this disease, these data add to the arsenal of strategies that will be required to tackle limitations of CAR T-cell therapies for the treatment of advanced liquid and solid tumors.
Importantly, despite lymphoma being a different beast compared with prostate, pancreatic, ovarian and other solid tumors, these data inform the entire field of cancer research about the potential of incorporating related strategies to generate robust and durable therapeutic responses for the majority of patients. This is an exciting prospect.
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Ghafouri SN, et al. Abstract CT007. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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