CRISPR Therapeutics’ CAR-T Cell Therapy Registers Mixed Results in Cancer Trial

By Judy Ya-Hsuan Lin

CRISPR Therapeutics is a leading gene editing company focused on developing transformative gene-based medicines for serious diseases through its proprietary CRISPR/Cas9 platform. On October 21st, the company announced positive topline results from its ongoing Phase 1 CARBON trial, where its latest allogeneic CAR-T cell therapy, CTX110, demonstrated comparable efficacy to the early autologous CAR-T trials in patients with relapsed or refractory non-Hodgkin lymphoma who had been previously treated with at least two lines of therapy.

“We are highly encouraged by today’s data, which demonstrate the promise of allogeneic therapies in treating hematological malignancies,” said Samarth Kulkarni, Ph.D., Chief Executive Officer of CRISPR Therapeutics. “Over time, we believe CRISPR-edited allogeneic CAR-T has the potential to leapfrog autologous CAR-T and benefit much broader patient populations. We continue to enroll patients and look forward to additional data read-outs for this program and our other allogeneic CAR-T programs, CTX120™ and CTX130™, next year. We are grateful to the patients and investigators who have made this important research possible.”

However, a patient’s death in the trial has disappointed investors and dragged down the company’s stock price as much as 12.1%.

CARBON Trial

The Phase 1 CARBON clinical trial is an open-label, single-arm, multicenter study to evaluate the effectiveness and safety of CTX110, which specifically targets CD19+ B-cell malignancies. The trial comprises four different levels (30×106 as level one, 100×10⁶ as level two, 300×10⁶ as level three, and 600×10⁶ as level four) of CTX110, involving a total of 12 adults with relapsed or refractory non-Hodgkin lymphoma and with at least two lines of therapies before beginning this trial. Patients were infused with CTX110 after three days of lymphodepletion using fludarabine (30mg/m2/day) and cyclophosphamide (500mg/m2/day).

The primary endpoints were overall response rate and safety as measured by the incidence of dose-limiting toxicities (DLTs). The secondary endpoints were duration of response, remaining progression-free, and overall survival. The data assessment cut-off date was September 28, 2020.

Among the 12 patients enrolled, “deep responses” were achieved by four patients, indicating how effective CTX110 was. Two of the four patients were at the third-highest dose level of 300×10⁶ CAR-T cells. Deep responses led to complete resolution of extranodal disease, normalization of all nodal disease to 1.5 cm or smaller, and a Deauville score of 2 or lower. Besides, one of the patients with 30% lymphoblasts became completely clear after infusion.

No DLTs, Graft-vs-Host Disease (GvHD), or infusion reactions to either lymphodepleting chemotherapy or CTX110 were observed in terms of safety. However, a 30% rate of Grade 2 or below Cytokine Release Syndrome (CRS) was resolved with tocilizumab and a 10% rate of Grade 2 Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS); fortunately, improvements were seen within one day after standard interventions. Although two additional severe side-effects, periorbital cellulitis, and febrile neutropenia, took place after CTX110 infusion, these too were resolved and later classified as irrelevant to disease progression or CTX110.

Give In Or Move Forward?

One of the major challenges CRISPR Therapeutics faces now is the efficacy of CTX001 is comparable to currently existing treatments. For instance, Gilead Sciences’ Yescarata demonstrated complete remission for 51 out of 101 non-Hodgkin lymphoma patients with a one-time dosage. In contrast, at least one of the patients administered CTX110 received more than one dose and failed to generate the desired effect.

Another obstacle is the death of one patient treated at the fourth (highest) dose level of 600×106 CAR-T cells about two months after the CTX110 infusion. According to CRISPR, the patient developed cytokine release syndrome (CRS) on the fifth day after infusion, but on Day 25, a PET/CT assessment showed that the patient subsequently achieved complete response. However, that patient’s condition worsened with febrile neutropenia, symptoms of short-term memory loss and confusion, as well as symptoms progressing to significant obtundation that required intubation. The patient was also found to have reactivation of HHV-6 (human herpesvirus 6) and HHV-6 encephalitis.

Nevertheless, Oncologists still harbor hopes for CTX110 because it sets a precedent in many ways. For one, CTX110 is an autologous therapy that engineers a patient’s own stem cell to recognize and fight against the same individual’s cancer. This makes CTX110 more compatible with donors, achieving a 0% of GvHD despite high HLA (human leukocyte antigen) mismatch between allogeneic CAR-T donors and the owner itself. Additionally, it is worthy for oncologists to know more about CTX110 and the newest allogeneic CAR-T programs developed through CRISPR’s pipeline.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: CRISPR, Vertex’s Gene Editing Based Therapy, CTX001 Prospers in Hemoglobinopathy Trials

References

1. http://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-reports-positive-top-line-results-its-phase

Author

Judy Ya-Hsuan Lin

Success is the ability to go from one failure to another with no loss of enthusiasm.