CRISPR's CTX110 CAR-T therapy shows promise in B-cell malignancies, but one death reported in early trial

CRISPR Therapeutics on Wednesday unveiled top-line results from a Phase I trial showing early evidence of anti-tumour activity with CTX110, the company's allogeneic CAR-T cell therapy targeting CD19+ B-cell malignancies. Joseph McGuirk, investigator in the CARBON study, said that "from this early data read-out, CTX110 has shown dose-dependent efficacy and response rates that are comparable to the early autologous CAR-T trials." He added that the therapy's "acceptable safety profile [for the three lower tested doses]…could make CAR-Ts more widely accessible," although a study participant treated at the highest dose died. CRISPR shares fell as much as 12.1% on the news.

The ongoing single-arm trial tested four dose levels of CTX110 in a cohort of 12 adults with relapsed or refractory non-Hodgkin lymphoma who had received at least two prior lines of therapy. Patients were infused with CTX110 following three days of lymphodepletion using fludarabine and cyclophosphamide. The primary endpoints were overall response rate and safety as measured by the incidence of dose limiting toxicities (DLTs), while key secondary goals include duration of response, progression-free survival and overall survival. This analysis reports on the 11 patients who completed at least their one-month assessment as of the September 28 data cut-off.

'Deep responses' in four patients

Complete responses (CR) were achieved by four participants in all, including two of four patients who were treated at the third highest dose level of 300x106 CAR+ T cells. According to CRISPR, the four patients who achieved CR had "deep responses, including complete resolution of extranodal disease, normalisation of all nodal disease to 1.5 cm or smaller, and a Deauville score of 2 or lower." The company noted that one of the CR patients who had 30% lymphoblasts in the bone marrow achieved complete clearance after CTX110 infusion. Further, CR was attained in patients with diffuse large B-cell lymphoma and with transformed follicular lymphoma, as well as in those who were primary refractory and who had relapsed after autologous stem-cell transplant.

High-dose patient dies

However, the single patient who was treated at the fourth and highest dose level of 600x106 CAR+ T cells died nearly two months after CTX110 infusion. According to CRISPR, the patient in question developed cytokine release syndrome (CRS) on day five post-infusion that resolved five days later, with a PET/CT assessment showing the patient subsequently achieved CR at day 25. The patient was hospitalised the next day with febrile neutropenia and developed symptoms of short-term memory loss and confusion, with symptoms progressing to significant obtundation that required intubation. CRISPR said the patient was later found to have reactivation of HHV-6 and HHV-6 encephalitis, and died 52 days after CTX110 infusion following a decision to withdraw supportive care.

The company said no DLTs were observed among patients treated at dose levels one to three, including no cases of graft-vs-host disease, and no infusion reactions to either lymphodepleting chemotherapy or CTX110. Among patients in these dose groups, there were three cases of CRS that resolved. One patient had immune effector cell-associated neurotoxicity syndrome that improved within 24 hours, while two cases of periorbital cellulitis and febrile neutropenia also resolved and were considered unrelated to disease progression or CTX110.

McGuirk stated that "while longer follow-up is required, these early data support the potential for CTX110 to become an effective 'off-the-shelf 'CAR-T therapy for patients with relapsed or refractory B-cell malignancies."

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