CRISPR’s CAR-T Cell Therapy Shows Promise in Clinical Trial

CRISPR Therapeutics, recently announced positive top-line results from its ongoing Phase 1 clinical trial evaluating the safety and efficacy of its allogeneic CAR-T cell therapy that targets CD19+B-cell malignancies. 

The CARBON trial, an open-label, multicenter study, enrolled 12 adult patients with relapsed or refractory non-Hodgkin lymphoma who previously received two lines of therapy. The trial dosed some of their patients with the therapy known as CTX110.

Out of all 12 patients, there were no dose limiting toxicities found. There was, however, early evidence of dose-dependent anti-tumor activity. 

“We are highly encouraged by today’s data, which demonstrate the promise of allogeneic therapies in treating hematological malignancies,” Samarth Kulkarni, PhD, chief executive officer of CRISPR Therapeutics, said in the announcement.

“Over time, we believe CRISPR-edited allogeneic CAR-T has the potential to leapfrog autologous CAR-T and benefit much broader patient populations.”

Patients received one of four dose levels of CTX110 after three days of lymphodepletion using fludarabine (30 milligrams/day) and cyclophosphamide (500 milligrams/day). 

The primary endpoints included safety as measured by the incidence of dose limiting toxicities and overall response rate. Key secondary endpoints were duration of response, progression-free survival, and overall survival.

Complete response rate was achieved in Dose Levels 2, 3, and 4. At Dose Level 3, two out of four patients had complete response and still remain in complete response. 

These four patients had deep responses, including the complete resolution of extranodal disease, normalization of all nodal disease, and a Deauville score of two or lower, researchers highlighted.

At Dose Level 2 and above, CTX110 was detected at multiple points in all patients, with the highest expansion reported between one and two weeks. And one patient with 30 percent lymphoblasts in the bone marrow saw complete clearance after CTX110 infusion. 

Notably, cells were detected as late as 180 days post-infusion​.

"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. Furthermore, CTX110 had an acceptable safety profile, which could make CAR-Ts more widely accessible,” said Joseph McGuirk, DO, professor of medicine and division director of hematologic malignancies and cellular therapeutics at the University of Kansas Medical Center and investigator of the trial.

Other findings from the trial include:

·       In Dose Levels 1 through3, there were no reports of Graft-vs-Host Disease despite high human leukocyte antigen (HLA) mismatch between CAR-T donors and patients. There were also no infusion reactions to chemotherapy or CTX110. 

·       Additionally, Cytokine Release Syndrome occurred in 30 percent of patients and resolved tocilizumab administration. Ten percent of patients had Grade 2 Immune Effector Cell-Associated Neurotoxicity Syndrome that improved within one day and with standard care.There were only two serious adverse events reported after CTX110 infusion, which were both resolved and determined to be separate from disease progression or cell therapy. 

Experts believe that the next generation of cell therapies holds significant promise for patients because it creates a point-of-care that may potentially cure many illnesses. 

But despite the great promise that cell therapies bring to modern medicine, there are several challenges of cell therapy development because of differences between the set of capabilities needed for CAR T cell therapy development and the development of more traditional types of treatments.

One way to combat this challenge, according to the Alliance of Regenerative Medicine, is to turn to professional manufacturing organizations to help develop and manage manufacturing programs. 

Cell therapy also requires increased patient engagement and support during the long treatment process.

But because most therapies receive either the FDA’s Regenerative Medicine Advanced Therapy Designation or breakthrough designations, there is a slight increase in small clinical trials, which leads to a shortage of experienced physicians who are equipped to run cell therapy trials. 

Therefore, experts suggest that researchers scale operations to meet these needs and increase patient engagement.