Higher disease burden leads to poorer CAR-T outcomes in large B-cell lymphoma
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Immune dysregulation resulting from high tumor burden appeared associated with poor chimeric antigen receptor T-cell expansion and resistance among patients with diffuse large B-cell lymphoma, according to study results published in Blood.
Patients with higher tumor burden demonstrated chronic interferon signaling within the tumor and high cytokine levels, results of the observational study showed.
“Patients with lymphoma who have large tumors also have a proinflammatory state where they have elevated cytokines and suppressive myeloid cells in the blood; they also have suppressive myeloid cells within the tumor,” Frederick L. Locke, MD, co-leader of the immune-oncology program and vice chair of the department of blood and marrow transplant and cellular immunotherapy at Moffitt Cancer Center, and a member of the Cell Therapy Next Peer Perspective Board, told Healio. “The presence of elevated cytokines and suppressive myeloid cells has been associated with lack of expansion of CAR T cells in the blood of patients and a lack of efficacy for the treatment.”
Locke and colleagues prospectively collected blood and tumor tissue samples from 105 patients who received axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), also known as axi-cel. Samples were obtained before and after infusion.
Eighty-five patients received axi-cel as standard of care, 14 as part of a clinical trial and six as part of the ZUMA-9 expanded access trial.
The researchers divided patients into two groups: those who had a durable response to therapy and remained in remission after minimum follow-up of 6 months (n = 42; median age, 62 years; range, 19-78; 54.8% men) and those who lacked a durable response and died or experienced disease relapse (n = 59; median age, 64 years; range, 30-80; 74.6% men).
The results showed patients who lacked a durable response to axi-cel had higher expression of genes that are known targets of tumor interferon signaling.
An analysis of the frequency of monocytic myeloid-derived suppressor cells in patients’ blood revealed higher levels at baseline in patients who lacked a durable response to therapy compared with durable responders.
Tumor expression of interferon signaling and high blood levels of monocytic myeloid-derived suppressor cells, interleukin-6 and ferritin all appeared associated with lack of durable response to axi-cel, according to the researchers.
Patients with a durable response had median peak axi-cel levels that were 10-fold higher than those of nondurable responders (P = .01). Blood monocytic myeloid-derived suppressor cell levels negatively correlated with peak axi-cel levels, researchers noted.
Additionally, patients with high (greater than 250 cells/µl) median baseline monocytic myeloid-derived suppressor cell levels had fourfold lower peak expansion of CAR T cells than patients who had lower baseline levels (P = .02).
Patients with high metabolic tumor volume (greater than 150 cc) had immune dysregulation characterized by significantly higher levels of serum inflammatory markers and tumor interferon signaling. Expression of interferon signaling genes also was highest among patients who had poor expansion of CAR T-cells after infusion.
The results indicate that measures to reduce both immune system inflammation and tumor burden before CAR T-cell therapy may improve outcomes after infusion, Locke said.
“One way we think we can improve the outcomes of these patients is to reduce the amount of tumor burden by irradiating the patient prior to CAR T-cell therapy in areas of bulky disease,” he told Healio.
Locke’s group has published results on the feasibility of radiation as a bridging therapy before axi-cel infusion for patients with DLBCL.
“Now we want to test out prospectively whether it actually improves outcomes,” he added.
Additionally, Locke and colleagues are looking to design a clinical trial aimed at reducing inflammation before CAR T-cell therapy.
“If inflammation is one of the key characteristics that leads to decreased efficacy, then drugs that interrupt inflammatory signaling pathways — in particular, interferon signaling — given before CAR T-cell therapy may reverse some of the suppressive effects of inflammation within the tumor microenvironment,” he said.
References:
Jain MD, et al. Blood. 2021;doi:10.1182/blood.2020007445.
Sim AJ, et al. Int J Radiat Oncol Biol Phys. 2019;doi:10.1016/j.ijrobp.2019.05.065.
For more information:
Frederick L. Locke, MD, can be reached at frederick.locke@moffitt.org.
Perspective
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Samantha Bucktrout, PhD
This study adds to the understanding of patient attributes — immune and tumor — that result in successful cellular therapy. What we need next is a comparative analysis of the cellular therapy product. These products are patient-derived, so immune “dysfunction” also could be evident in the cellular therapy product itself. Thus, this study highlights potential biomarkers of patient benefit, but we still have a way to go before uncovering deeper mechanistic insights that are needed to translate to improved therapies.
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