A New Target for Tisagenlecleucel: Primary Central Nervous System Lymphoma

Take-aways:

• Tisagenlecleucel was well-tolerated with manageable toxicity in patients with primary central nervous system lymphoma (PCNSL).
• In the absence of systemic disease, researchers observed effective peripheral blood expansion and trafficking of CAR T cells to the CNS compartment.
• These findings suggest that increasing access to this CAR T-cell therapy for patients with PCNSL may improve clinical outcomes in this population.

---

The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (tisa-cel) appeared to be safe and effective in a group of patients with highly refractory primary central nervous system lymphoma (PCNSL), according to a study published in Blood.

Previously, patients with PCNSL have been excluded from all pivotal studies of CAR T-cell therapies due to concerns about potential immune cell–associated neurotoxicity syndrome (ICANS). All three CAR T-cell therapies currently approved by the U.S. Food and Drug Administration for the treatment of lymphoma carry a limitation of use in the PCNSL population.

“Due to these exclusions, little is known about the treatment-related toxicities and therapeutic potential of the currently available commercial CD19-directed CAR T products in this challenging patient population,” corresponding author Matthew J. Frigault, MD, of the Massachusetts General Hospital Cancer Center, wrote.

Dr. Frigault and colleagues conducted a phase I/II clinical trial evaluating tisa-cel in 12 patients with relapsed PCNSL and significant unmet medical need. Initially, 13 patients were enrolled, but 1 patient elected to transition to hospice when their disease progressed following CAR T-cell manufacturing failure due to E. coli contamination.

At baseline, patients’ median age was 63 years (range, 34-81). Median time from leukapheresis to infusion with tisa-cel was 33 days (range, 27-37), and median time from infusion to data cutoff was 12.2 months (range, 3.64-23.5). Prior to study enrollment, patients had received a median of 4 prior lines of antineoplastic therapy (range, 2-9). All patients had disease that was refractory to first-line high-dose methotrexate, and 3 had previously received thiotepa-based autologous stem cell transplant (ASCT). All patients were refractory to Bruton tyrosine kinase (BTK) inhibitors and immunomodulatory drugs. Four had undergone prior partial radiotherapy.

The primary endpoints of the study were tolerability and toxicity, including grade and rate of cytokine release syndrome (CRS) and ICANS according to 2019 American Society of Transplantation and Cellular Therapy consensus criteria.

Overall response rate (ORR) and complete response (CR) rate represented secondary endpoints of the study. Responses were measured per International PCNSL Collaborative Group criteria, including MRI and CSF assessments occurring monthly for 6 months and quarterly thereafter for up to 24 months.

Incidence of ICANS and CRS are presented in Table 1. Grade 1 CRS was reported in 7 patients, with a median onset of 4 days following tisa-cel infusion (range, 1-5) and a median duration of 2 days (range, 2-8). ICANS was observed in 6 patients total at grade 1 (n, 3), grade 2 (n, 2), and grade 3 (n, 1). The median time of onset was 5 days (range, 3-11) and the median duration was 3 days (range, 1-11).

Six CRs and 1 partial response were observed. Median time to response was within 1 month, with best response by a median of 3.4 months. At data cutoff, 7 patients (58.3%) were alive and 3 had not experienced disease progression. Figure 1 shows magnetic resonance imaging of a patient who achieved a best response by month 4 after infusion. The study authors noted that all patients whose disease responded and subsequently progressed presented with new sites of CNS disease, rather than recurrence of prior lesions.

In all but 1 patient, tisa-cel expansion in peripheral blood was measurable by flow cytometry. This expansion occurred despite concurrent use of dexamethasone at time of infusion, Dr. Frigault noted. CAR T-cell trafficking into the cerebrospinal fluid (CSF) was observed in all patients with expansion in peripheral blood.

“Additional studies may need to explore earlier use of CAR T cells as a potential consolidative approach for relapsed or refractory PCNSL patients who are not eligible for high-dose therapy and ASCT,” Dr. Frigault wrote, “especially utilizing non-curative bridging strategies such as BTKi/ITKi and PD-1 checkpoint inhibitors.”

Disclosures: This research was supported by Novartis. Study authors report relationships with Novartis, the manufacturer of tisagenlecleucel.

Reference

Frigault MJ, Dietrich J, Gallagher KME, et al. Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase I/II clinical trial. Blood. 2022 Feb 15; doi: blood.2021014738.