Product composition, immune biomarkers linked to CAR-T efficacy
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Product attributes appeared associated with more potent and durable responses to axicabtagene ciloleucel among patients with follicular lymphoma, according to an analysis of the ZUMA-5 trial.
The results, presented during the virtual American Association for Cancer Research Annual Meeting, also showed certain pretreatment immune biomarkers were predictive of relapse after treatment with the chimeric antigen receptor T-cell therapy.
Axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead), also known as axi-cel, is an autologous, gene-edited CAR T-cell therapy that targets the CD19 protein on the surface of cancer cells. Last month the FDA approved axi-cel for adults with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.
“The key goal of this analysis is to further interrogate mechanisms of primary and secondary treatment failures,” Vicki Plaks, LLB, PhD, director of cell biology for Kite, told Healio.
Plaks and colleagues detailed the product attributes and pharmacologic characteristics associated with patient outcomes in the primary analysis of the ZUMA-5 trial. The phase 2 study evaluated axi-cel among patients with relapsed or refractory follicular lymphoma (n = 124) or marginal zone lymphoma (n = 22) who experienced disease progression after two or more lines of therapy.
This secondary analysis of the trial included product cell composition, blood levels of CAR T cells and serum levels of immune biomarkers taken from tumors (13 samples from 21 patients) after disease progression. Researchers also evaluated tumor biopsies for CD19 expression.
Median follow-up was 16.2 months for patients with follicular lymphoma and 11.4 months for those with marginal zone lymphoma.
As of data cutoff on March 12, 2020, mediation duration of response had not yet been reached for patients with follicular lymphoma and was 10.6 months for patients with marginal zone lymphoma.
Among patients with follicular lymphoma, results showed positive associations between an ongoing response to therapy and total infused CCR7+/CD45RA+ T cells (P = .0044), peak CAR T-cell levels (P = .0212) and peak levels of several immune biomarkers. These included the immune-modulating factor interferon-gamma; inflammatory markers interleukin (IL)-6, serum amyloid A and C-reactive protein; the homeostatic marker IL-2, and the chemokine CXCL10.
Relapse after axi-cel for follicular lymphoma appeared positively associated with higher levels of several pretreatment immune serum biomarkers, including the regulatory T cell-related chemokines CCL22/MDC and CCL17, immune-modulating factors IL-10 and IL-16, and inflammatory markers IL-2 receptor alpha and tumor necrosis factor-alpha. Researchers also observed associations of relapse after therapy with lover levels of CCR7+/CD45RA+ T cells in the axi-cel product.
Results of tumor biopsies showed all 14 patients eligible for evaluation had detectable CD19 expression, including 13 patients with follicular lymphoma.
“The fact that all evaluable relapses retained CD19 expression was somewhat surprising,” Plaks told Healio, adding that a previous report by Neelapu and colleagues showed approximately 30% of patients with aggressive lymphomas had CD19-negative relapses after axi-cel infusion.
In terms of safety, grade 2 or greater cytokine release syndrome appeared positively associated with total CCR7+/CD45RA+ T cells (P = .0398) in the axi-cel product and peak CAR T-cell levels (P < .0001) among patients with follicular lymphoma. Researchers reported similar associations of grade 3 or greater neurotoxicity with total CCR7+/CD45RA+ T cells (P = .0356) and peak CAR T-cell levels (P = .0032).
Patients with follicular lymphoma had higher pretreatment levels of CCL17 and lower post-infusion levels of several immune biomarkers compared with those who had marginal zone lymphoma.
The results suggest product composition and immune regulatory mechanisms may influence the clinical effectiveness of axi-cel in patients with follicular lymphoma, Plaks said.
“We are currently investigating the tumor microenvironment alongside product performance and serum biomarkers to further increase confidence in dose optimization, determine the feasibility of repeated dosing and elucidate what combination approaches and/or predictive biomarkers of response could be employed for axi-cel in patients with [indolent non-Hodgkin lymphoma],” she said. “These data will help us optimize treatments to maximize clinical benefit.”
References:
Neelapu SS, et al. Blood. 2019:doi;10.1182/blood-2019-126218.
Plaks V, et al. Abstract CT036. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
Perspective
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Lisa Butterfield, PhD
This study indicates that mechanisms of response and relapse differ between tumor types, and that although target antigen loss by the tumor is always a critical mechanism of resistance to examine, other product and systemic immunity factors are more important. The functional attributes of the CD45+/CCR7+ cells will be important to profile. The systemic cytokines identified also will be critical to examine over time relative to product infusion and response or relapse.
Perspective
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Matthew Mei, MD
CD19-directed CAR T-cell therapy has transformed the therapeutic landscape of relapsed and refractory B-cell NHL.
After its initial FDA approval for the indication in 2017, axi-cel obtained FDA approval for relapsed or refractory follicular lymphoma based on results of the ZUMA-5 trial, which enrolled patients with two indolent NHL histologies — follicular lymphoma and marginal zone lymphoma. Although the preliminary results were very impressive (76% complete remission rate, 92% overall response rate), disease relapse still occurred in many patients and a significantly different incidence of neurotoxicity was seen between the follicular lymphoma and marginal zone lymphoma cohorts. Further, the long-term durability of responses remains unclear.
Much research has centered around understanding the biological processes that underlie disease resistance and the unique toxicities seen with CAR T-cell therapy, including cytokine release syndrome and neurotoxicity. This study identified multiple potential biomarkers correlated with disease response and toxicity among patients with indolent NHL. Notably, CAR-T product composition, disease burden and patient-specific immunological markers all appear to contribute, whereas loss of the target antigen (CD19) was not a factor in disease relapse.
Further improvements in CAR T-cell therapy will require a deeper understanding of the complicated interplay between an immune system already perturbed by previous chemoimmunotherapy, the infused CAR-T product and the cancer itself. This work underscores the fact that all three components play a critical role in mediating both the dramatic responses and toxicities seen with CAR T-cell therapy. The progress to date is nothing short of astounding, but there is still much room left for further optimization of CAR-T.
Reference:
Jacobson C, et al. Abstract 700. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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Plaks V, et al. Abstract CT036. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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