No CNS sanctuary for lymphoma from CAR T

In this issue of Blood, Frigault et al¹ report that anti-CD19 chimeric antigen receptor–modified T cells (CAR T cells) can proliferate in the blood, traffic to the central nervous system (CNS), and successfully target primary central nervous system lymphoma (PCNSL). Complete remissions were observed in this patient group with historically poor outcomes.

PCNSL is a rare disease, comprising 3% of primary brain tumors in the United States. Unfortunately, only about 50% of patients with PCNSL will remain disease free after first-line methotrexate-based therapy.² For those patients with relapsed/refractory PCNSL, there is no standard curative approach. In a significant number of patients, with multiply relapsed or refractory systemic B-cell lymphomas,³ CAR T-cell therapies targeting CD19 can achieve durable remissions and are commercially available.^4,5 A unique toxicity of CAR T cells is neurologic, termed immune effector cell–associated neurotoxicity syndrome or ICANS.^4,5 Even in the absence of CNS involvement by lymphoma, CAR T cells are known to traffic into the CNS, and ICANS has been observed.⁶ Although CD19 is traditionally considered a lineage-specific B-cell marker, pericytes, which surround endothelial cells along the walls of capillaries as part of the blood-brain barrier, may also express the isoform of CD19 targeted by CAR T cells; this is thought to possibly contribute to the neurologic toxicity of CAR T cells.⁷ For these reasons, patients with PCNSL were specifically excluded from registrational CAR-T trials owing to concerns for precipitation or exacerbation of ICANS. Although 7 patients with secondary CNS involvement were included in 1 registrational trial,⁵ data to support CAR T cell use in PCNSL are limited to small retrospective case series and post hoc analyses of prospective clinical trials.^8,9

In this study, Frigault et al present results of a single-center, prospective study of tisagenlecleucel (anti-CD19, 4-1BB, CD3ζ CAR T cells) in patients with PCNSL relapsed after, refractory to, or ineligible for standard first-line high-dose methotrexate-based therapy. This is the first report of a prospective clinical trial examining commercially available CD19-directed CAR T cells in patients with PCNSL. Corticosteroids, up to dexamethasone 4 mg daily or equivalent, were permitted during leukapheresis, as well as prior to, during, and after CAR T-cell infusion. The primary endpoint was safety. Secondary endpoints included overall and complete response rates. Twelve patients received tisagenlecleucel, which was generally well tolerated. One of 12 (8%) patients had grade 3 ICANS; severe cytokine release syndrome was not observed. The authors observed that CAR T cells infused IV expanded in blood and trafficked to the CNS, with responders having higher levels of CAR T cells in cerebrospinal fluid. At 12 months’ median follow-up, overall response rate is 7/12 (58%) with a continuing response in 3/12 (25%) patients at the time of reporting (see figure).

The number of patients treated on this study is small; however, PCNSL is a rare disease. Thus, a small sample size is expected. Although the rate of severe neurologic toxicity in this study is comparable to the historical rate for tisagenlecleucel in systemic lymphoma, it is noteworthy that 50% (6/12) of patients developed some degree of mild to moderate neurologic toxicity.¹ From a historical perspective, fewer (21%) patients in the registrational trial of tisagenlecleucel, JULIET, for systemic large B-cell lymphomas had any grade neurologic toxicity.⁴ The concurrent use of corticosteroids in 25% of patients on this trial would be expected to bias toward lower rates of neurotoxicity. The timing of neurologic toxicity reported in this study appears comparable to JULIET (4 vs 6 days after CAR T-cell infusion, respectively); however, the median duration of neurologic toxicity was shorter (5 vs 14 days, respectively). This study’s shorter duration of neurotoxicity may reflect the evolving practice of early initiation of corticosteroids at onset of neurologic toxicity.

This study confirms CAR T-cell expansion in peripheral blood in the absence of systemic lymphoma, an observation previously reported in patients with systemic lymphoma who received CAR T cells while in complete remission.¹⁰ It also allays the theoretical concern that CAR T cells might not expand adequately in B-cell–depleted patients with isolated CNS tumors. Similar to some prior studies of CAR T-cell therapy in systemic lymphoma that described an association between higher CAR T-cell levels in peripheral blood and efficacy,⁵ the authors observed higher CAR transgene levels in the cerebrospinal fluid of patients who achieved complete remission.

The patients enrolled on this study were a poor-prognosis group, including 5 of 12 (42%) with an Eastern Cooperative Oncology Group performance status of 2 or greater, a median of 4 prior lines of therapy (range: 2-9), and all had lymphoma progression after a Bruton tyrosine kinase inhibitor (BTKi), an active therapeutic class for PCNSL. Despite these unfavorable characteristics, 6 of 12 (50%) patients achieved complete responses with 3 of 12 (25%) still in remission at 1 year. These results are particularly encouraging for a group of patients with previously described response durations of 2 to 3 months.² It is also noteworthy that concurrent dexamethasone did not appear to abrogate the expansion or efficacy of CAR T cells, which is a theoretical concern among physicians administering CAR T.

These results are significant and suggest a path forward for treatment of relapsed/refractory PCNSL, a disease that often has a poor outcome and represents an unmet medical need. In addition, this study provides a signal that CAR T cells may become a compelling backbone with which to pair other agents that are active in PCNSL and compatible with T-cell–based therapy, such as BTKi, immunomodulatory drugs (IMiDs), and programmed cell death protein 1 (PD-1) blockade. We look forward to future studies of earlier application of CAR T cells for treatment of PCNSL, optimization of bridging therapy to control CNS lymphoma before CAR T-cell infusion, novel approaches to monitoring neurologic toxicity in patients with preexisting focal neurologic deficits, and CAR T cells in combination with other active therapies for PCNSL.