MSK's CAR Trials Halted Temporarily Amid Safety Review

Five early-phase clinical trials exploring chimeric antigen receptor (CAR) T-cell therapy have been suspended temporarily in response to the deaths of 2 patients with adult B-cell acute lymphoblastic leukemia

Renier J. Brentjens, MD,

Five early-phase clinical trials exploring chimeric antigen receptor (CAR) T-cell therapy were suspended temporarily in response to the deaths of 2 patients with adult B-cell acute lymphoblastic leukemia (ALL), but safety protocols were amended and enrollment is expected to resume soon, according to one of the research leaders (Update: The clinical hold was lifted April 19).

Renier J. Brentjens, MD, PhD, director of Cellular Therapeutics at Memorial Sloan Kettering (MSK) Cancer Center in New York City, said in an interview that MSK halted the trials as part of a voluntary and routine review of study procedures. He said the FDA supported the proposed amendments, as does the Institutional Review Board at MSK, and that he expects the trials will reopen to enrollment in the next 7-10 days (Interview conducted April 9).

“We don’t necessarily have any direct proof that the T cells precipitated these deaths,” said Brentjens. “The morbidity and mortality in this patient population is quite high. Nonetheless, as a matter of routine at our institution, we chose to put a hold on these studies so that we could amend the studies to try and minimize the risk of any T-cell related toxicity, especially in the context of the cytokine release syndrome [CRS].”

CAR T-cell technology is a form of adoptive cell therapy in which the patient’s T cells are cultured and then primed to specifically recognize target tumor cells, prior to infusion back into the patient. The 19-28z CAR T cells that MSK is exploring are engineered to express a CAR that recognizes the CD19 protein, which is expressed on the surface of the vast majority of B-cell malignancies.

CRS is a common phenomenon observed with T-cell therapies. Upon infusion into the patient, the T cells expand and cytokines are released, causing systemic symptoms such as fever, nausea, chills, hypotension, headache and rash, among others. CRS cannot be entirely prevented and is typically fully reversible; in fact, CRS is a sign that the treatment in working. However, severe cases of CRS may require therapeutic intervention and could exacerbate preexisting medical conditions.

Brentjens said the suggested amendments to the treatment protocol were to reduce T-cell dosage, treat patients at an earlier time point, and preclude patients with significant cardiac disease from enrollment, as well as preclude patients from additional infusions if they experience significant central nervous system toxicity at the time of the first infusion.

In all, 10 of the 22 patients with adult B-cell ALL treated so far with the CAR therapy in a phase I study at MSK have died, said Brentjens. Six of these patients relapsed or were refractory to treatment, and two more died from complications that arose from allogeneic bone marrow transplantation, to which patients were transitioned after CAR therapy.

The 2 patients whose deaths prompted the review died within 2 weeks of administration of CAR T-cell therapy. One patient had a history of cardiac failure and the other developed persistent seizures during the second infusion of cells, said Brentjens.

Brentjens said the safety review is “not motivated by concern that the therapy is overly toxic, but motivated by idea of modulating therapy in such a way that we minimize the cytokine release syndrome and treat patients who do not have preexisting medical conditions that could be exacerbated by CRS.”

In fact, results from this study showed the best response rates ever reported for this ALL patient population, according to results presented at the American Association of Cancer Research Annual Meeting in San Diego on April 6. Among 16 patients evaluated for efficacy, the overall response rate was 88%.

Brentjens said the toxicities observed in adult patients with ALL have not been experienced in MSK’s other trials of 19-28z CAR T cells. However, all 4 trials were suspended “to give us the opportunity to harmonize all the clinical trials so that the standards, enrollment criteria, and treatment doses are appropriately modified in every single one of our trials,” said Brentjens.

Specifically, the trials that were suspended included phase I clinical trials evaluating the CAR therapy in patients aged 18 years and older with B-cell ALL (NCT01044069); in pediatric and young adult patients with relapsed B-cell ALL (NCT01860937); in adults with relapsed and refractory aggressive B-cell non-Hodgkin lymphoma (NCT01840566); and in adults with chronic lymphocytic (CLL) (NCT01416974). In addition, a phase I/II trial in adults with CLL or indolent B-cell lymphomas also was halted (NCT00466531).

The prospect that CAR therapy can deliver significant clinical benefits for patients with hematologic malignancies has prompted much excitement in recent months.

MSK is partnering with the Fred Hutchinson Cancer Research Center and The Seattle Children’s Research Institute to develop T-cell engineering immunotherapies through Juno Therapeutics Inc, which was launched in December with $120 million in private financing that is believed to be one of the largest investments ever made in a biotech startup.

Brentjens, who is among Juno’s founding scientists, said the temporary clinical trial suspension at MSK would not affect other ongoing research. In addition to CAR therapy, the partnership also is exploring T-cell receptor (TCR) technology that targets antigens in association with human leukocyte antigen (HLA) cell-surface molecules.