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CAR T-cell Therapy Feasible for Active Secondary CNS Lymphoma

Key findings

  • The Cellular Therapy and Neuro-Oncology Program at Massachusetts General Hospital has reported the experience of eight patients who were treated with tisagenlecleucel for high-grade B-cell lymphoma with secondary central nervous system (CNS) involvement
  • No patient required tocilizumab or high-dose steroids for management of cytokine release syndrome and/or neurotoxicity
  • Active systemic disease was not required for CAR T-cell expansion and disease response, suggesting CAR T-cells can sufficiently traffic to the CNS
  • Mass General is recruiting for a pilot study of tisagenlecleucel in primary CNS lymphoma

Axicabtagene ciloleucel and tisagenlecleucel are chimeric antigen receptor (CAR) T-cell therapies approved for the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma. Because of concerns about potential neurotoxicity, patients with active central nervous system (CNS) involvement were excluded from the pivotal studies of both drugs.

In Blood, Matthew Frigault, MD, oncologist in the Cellular Therapy Service at the Massachusetts General Hospital Cancer Center, Jorg Dietrich, MD, PhD, director of the Cancer & Neurotoxicity Clinic and Brain Repair Research Program, Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program, and colleagues report the experience of eight patients who were treated with tisagenlecleucel for high-grade B-cell lymphoma with secondary CNS involvement.

Patient Characteristics

The median patient age was 50 (range, 17–79). At the time of CAR T-cell therapy:

  • Three patients had parenchymal involvement, three had leptomeningeal involvement and two had both
  • All were receiving CNS-directed therapy
  • Two had additional systemic diseases
  • All but one had ECOG performance status of 0 to 2

Treatment

Patients received a single infusion of tisagenlecleucel following lymphodepleting chemotherapy. All received prophylactic anticonvulsants. Initial response assessments were made on day 28 following infusion (±2 days). No patient received growth factor support before day 17.

Results

No patient required tocilizumab or high-dose steroids for the management of cytokine release syndrome and/or neurotoxicity.

Active systemic disease was not required for CAR T-cell expansion and disease response, suggesting CAR T-cells can sufficiently traffic to the CNS. Treatment responses were seen as early as three to four weeks after infusion. The authors summarize two representative cases of response.

Two patients died of progressive disease. One of them had no clinical evidence of inflammatory markers suggestive of CAR T-cell expansion and died on day 25. On autopsy, there was no significant extension of CAR T-cells into the parenchyma surrounding the tumor.

The other patient died on day 3. He had received six previous lines of therapy, and before chemotherapy, he had required aggressive management of elevated intracranial pressure. His case emphasizes the importance of offering CAR T-cell therapy earlier and during a period of clinical stability.

Looking Ahead

Dr. Frigault, Dr. Dietrich and Dr. Maus are now leading a Phase 1 clinical trial testing the efficacy of tisagenlecleucel in patients with primary central nervous system lymphoma and are optimistic that this will set the stage for a larger Phase II study in this patient population.

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