American Association for Cancer Research Annual Meeting

American Association for Cancer Research Annual Meeting

Perspective from Lisa Butterfield, PhD
Perspective from Matthew Mei, MD
Source:

Plaks V, et al. Abstract CT036. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.

Disclosures: Kite Pharma sponsored the study. Plaks reports employment with and stock ownership/travel support from Kite Pharma, and patents, royalties or other intellectual property from Genentech. Please see the abstract for all other researchers’ relevant financial disclosures.
April 16, 2021
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Product composition, immune biomarkers linked to CAR-T efficacy

Perspective from Lisa Butterfield, PhD
Perspective from Matthew Mei, MD
Source:

Plaks V, et al. Abstract CT036. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.

Disclosures: Kite Pharma sponsored the study. Plaks reports employment with and stock ownership/travel support from Kite Pharma, and patents, royalties or other intellectual property from Genentech. Please see the abstract for all other researchers’ relevant financial disclosures.
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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.

Product attributes appeared associated with more potent and durable responses to axi--cel.
Content derived from Plaks V, et al. Abstract CT036. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.

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.

Vicki Plaks, LLB, PhD
Vicki Plaks

“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.