Optimizing CAR T for Patients With BCL and CNS Involvement

CAR T targeting CD19 antigen

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To improve patient outcomes from CD19-targeting chimeric antigen receptor (CAR) T-cell therapy for B-cell lymphoma with secondary central nervous system involvement (SCNSL), investigators are calling for future studies to consider CAR T numbers, phenotype, and function in the various body compartments of these patients, according to findings published in Cancer Immunology and Immunotherapy. Doing so, they add, may help to prevent off-target effects and optimize tumor-reactive CAR T cells.

“Historically, SCNSL patients have been excluded from clinical trials,” the study authors wrote, “highlighting the importance of reporting case series and conducting small-scale clinical trials to elucidate new therapeutic avenues.”

Patient outcomes were analyzed using samples of their blood and cerebrospinal fluid (CSF), after which peripheral blood mononuclear cells were isolated; histologic sections from tissue samples underwent immunohistochemical and in situ hybridization; and stained samples were analyzed using flow cytometry.

The first patient was a 38-year-old man who had Burkitt lymphoma and CNS progression. His treatments encompassed whole-brain radiation (WBR), lymphodepleting chemotherapy, and lisocabtagene maraleucel (liso-cel). Lethargy was markedly increased by the eighth day after CAR T receipt, and by day 10, he transitioned to hospice care after a brain MRI showed progressive disease.

Patient 2 was a 48-year-old man who had CD19-expressing non–germinal center B-cell–like diffuse large B-cell lymphoma with CNS relapse. He failed several lines of therapy before dexamethasone administration for brain edema; that therapy was tapered before lymphodepletion and liso-cel infusion. After developing several serious adverse effects (neurotoxicity, hemophagocytic lymphohistiocytosis, and elevated C-reactive protein [CRP], ferritin, and triglycerides) that did not improve, he was transitioned to hospice care at day 47 post CAR T.

The third patient was a 32-year-old man with relapsed high-grade B-cell lymphoma, with previous failure of axicabtagene ciloleucel (axi-cel). He received WBR, lymphodepletion, and liso-cel. After 8 months of neither cytokine release syndrome nor immune effector cell-associated neurotoxicity syndrome (ICANS), his lymphoma relapsed. He had a subsequent complete remission when he received rituximab, gemcitabine, oxaliplatin, and zilovertamab vedotin as part of a clinical trial, which was followed by an allogeneic stem cell transplant.

Patient 4 was a 33-year-old man with refractory Burkitt lymphoma with CNS involvement. He received lymphodepletion and axi-cel before developing grade 2 ICANS and having seizures. At day 21 post CAR T, lymphoma cells were detected in his CSF, and at day 26, new parenchymal lesions. Despite the ICANS improving with steroids, he died by day 50 post CAR T.

The investigators noted that absolute lymphocyte and neutrophil counts substantially decreased in all patients after lymphodepleting chemotherapy, but that these counts soon recovered. Further, 3 patients had just a transient increase in their CRP 1 week post CAR T, and in all, ferritin levels remained low. Only in patient 4 did peripheral blood CAR T cells have an approximate 100-fold increase in the first week after CAR T.

“From a clinical perspective, our results indicate a very heterogenous response pattern to CD19 CAR-T in patients with SCNSL,” the authors wrote. “It is important to keep in mind that, in addition to gaining highly restricted access to the CNS, tumor-specific T cells have to overcome an abundance of local immunosuppressive mechanisms leading to T-cell senescence, exhaustion, and apoptosis.”

Future investigations, they strongly recommend, need to test how to improve localized CAR T for the CNS and how to stimulate highly tumor-reactive T cell delivery into the CNS—all while preventing off-target effects.

Reference

Kline K, Luetkens T, Koka R, et al. Treatment of secondary CNS lymphoma using CD19‑targeted chimeric antigen receptor (CAR) T cells. Cancer Immunol Immunother. 2024;73(3):45. doi:10.1007/s00262-023-03619-9