Intravenously Administered CD19-Directed CAR T Cells Safe, Potentially Effective in Primary CNS Lymphoma

Intravenously administered CD19-directed chimeric antigen receptor (CAR) T-cell therapy was found to be safe and associated with high levels of complete remission (CR) in patients with primary central nervous system lymphoma (PCNSL), according to findings from a case series published in Blood Advances.

Study authors, led by Tanya Siddiqi, MD, of City of Hope in Duarte, California, conducted a retrospective analysis of a cohort enrolled in an ongoing phase I clinical trial investigating the safety and optimal dose of cellular immunotherapy in patients with previously treated lymphoid malignancies. The cohort in the present analysis included five adults with either recurrent, progressive, or refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia with confirmed CD19-positive disease. All five patients had CNS involvement of their disease.

Prior to administering CD19-directed CAR T cells, patients received a fludarabine/cyclophosphamide-based lymphodepletion regimen. The CAR T cells were produced from autologous T naïve/memory cells that were transduced with a CAR construct containing a CD28 costimulatory domain and co-expressing truncated epidermal growth factor receptor, the researchers explained.

The investigators tested two dose levels of the studied therapy:

  • 200 million CAR-positive cells (n=3)
  • 600 million CAR-positive cells (n=2)

Each patient received levetiracetam to prevent seizures. The researchers used positron emission tomography (PET) and brain magnetic resonance imaging (MRI) scans on day 28 post–CAR T-cell infusion to assess initial disease response. CR was defined as complete resolution of enhancing lesions on MRI.

At enrollment, all patients demonstrated evidence of diffuse large B-cell lymphoma. Participants’ median age was 49 years (range = 42-53 years). All participants were women and had received a median of five prior therapies.

Each patient developed cytokine release syndrome (CRS). Three patients experienced grade 1 CNS and two cases were of grade 2 severity. Two of five patients were treated with tocilizumab and dexamethasone. The remaining three patients did not require treatment for CRS or neurotoxicity. The researchers found that the highest-grade toxicity (grade 3 neurotoxicity) manifested in one patient as headache lasting three days, starting at five days post-infusion, with severe pain limiting self-care for at least one day. This patient also had concurrent fever and cellulitis. Toxicities were reversible and tolerable, and there were no treatment-related deaths, the authors added.

At 28 days after infusion, three patients (60%) had achieved CR based on imaging and the remaining two patients showed evidence of stable disease. Of the patients with CR, one experienced disease progression at day 273, one subsequently went on maintenance treatment at day 43, and one remained in follow-up without maintenance therapy at day 520. Four of the five initial patients were still alive at the last assessment (the other patient was lost to follow-up).

Researchers collected blood specimens during the 28-day post-infusion period from four of the five patients. Analysis revealed CAR T-cell expansion by flow cytometry as well as quantitative polymerase chain reaction. The investigators also noted a lack of CD19-positive B cells or systemic lymphoma.

An image series for a patient in CR showed a lesion prior to CAR T-cell infusion that was absent at 28 days following infusion. The investigators added that patients in CR also showed small lesions at baseline and hinted to the possibility “that disease burden played a role in response to intravenous CD19-directed CAR T-cell therapy in the context of PCNSL.”
Cerebrospinal fluid (CSF) from one patient showed presence of CAR T cells and demonstrated that the intravenously administered therapy “could traffic to the CSF despite the absence of systemic lymphoma,” according to the researchers.

Limitations of this study included its small sample size and lack of a comparator or control arm. Additionally, the researchers explained that the study “was originally designed for patients with systemic disease and thus, several aspects of the trial were not ideal for patients with PCNSL.” Despite these limitations, the investigators added that the data from this preliminary cohort suggest intravenously administered CD19-directed CAR T-cell therapy holds promise for the PCNSL patient population.

Study authors report no relevant conflicts of interest.

Reference

Siddiqi T, Wang X, Blanchard MS, et al. CD19-directed CAR T-cell therapy for treatment of primary CNS lymphoma. Blood Adv. 2021;5(20):4059-4063.