David Chang, MD, PhD
Treatment with KTE-C19, a CD19-targeted CAR-modified T cell therapy, demonstrated an objective response rate (ORR) of 92% in patients with advanced B-cell malignancies, according to findings from an ongoing phase I/IIa trial published in the Journal of Clinical Oncology.
In the study, 15 patients with indolent B-cell malignancies and diffuse large B-cell lymphoma (DLBCL) were enrolled, with 13 evaluable for response. The complete remission (CR) rate was 61.5% and the partial remission (PR) rate was 30.8%. In evaluable patients with chemotherapy-refractory DLBCL (n = 7), the CR rate was 57.1%, with 75% of patients remaining in an ongoing remission at the time of the analysis (range 9—22 months).
KTE-C19, which is being developed collaboratively by Kite Pharma and the NCI, is manufactured through the genetic modification of autologous T cells to express an anti-CD19 chimeric antigen receptor (CAR). Results from the phase I/IIa study initially generated excitement at the 2013 ASH Annual Meeting, along with reports from several other early studies exploring novel CAR-modified T cell therapies.
“To date, Kite and the NCI have conducted an extensive program to investigate personalized T cell immunotherapies for blood cancers and solid tumors, including in patients with refractory DLBCL,” David Chang, MD, PhD, the executive vice president of Research and Development and chief medical officer at Kite, said in a press release. “Both the high overall response rate and the durability of the complete remissions are noteworthy, and we believe our anti-CD19-CAR T cell approach holds great potential for the treatment of B cell malignancies, including those with aggressive, resistant disease for which there are no viable treatment options.”
In the ongoing trial, 15 patients were enrolled, with 9 patients having DLBCL and 6 with indolent B-cell malignancies. In total, 8 of the 9 patients enrolled with DLBCL were chemotherapy-refractory and 7 of the 9 met the criteria for high-risk by international prognostic factors. Four patients had chronic lymphocytic leukemia.
A conditioning regimen of cyclophosphamide and fludarabine was administered prior to KTE-C19. Over the course of the study, the dose for KTE-C19 was reduced from 5 to 1 x 106 cells/kg. This condition regimen has been demonstrated to have antitumor activity.
All patients with indolent B-cell malignancies experienced an ORR. Overall, for 7 evaluable patients with DLBCL, 4 experienced a CR, 2 had a PR, and 1 patient had stable disease, for a 100% clinical benefit rate. Among patients with CLL (n = 4), 75% were in ongoing CRs confirmed by multicolor flow cytometry of the bone marrow.
Adverse events associated with KTE-C19 were most frequent in the first 2 weeks following the initiation of treatment. Overall, 27% of patients experienced grade 3/4 hypotension. All patients experienced some form of elevation in serum interferon gamma or IL-6; however, most patients did not develop elevations in serum tumor necrosis factor.
A number of neurologic symptoms were reported, following treatment with KTE-C19, including confusion and obtundation. One patient died suddenly as a result of an unknown cause 16 days after cell infusion.
“We are greatly encouraged by the strong results we have seen from our joint lead clinical program with the NCI,” Arie Belldegrun, MD, president and chief executive officer at Kite, said in a statement. “Based on this substantial progress, Kite plans to file an IND in the fourth quarter of this year to initiate a phase I/II single-arm multicenter clinical trial of KTE-C19 in patients with DLBCL who have failed two or more lines of therapy. We are excited to advance this promising therapy and anticipate commencing patient enrollment in our DLBCL clinical trial in the first half of 2015.”
Juno Therapeutics and Novartis are also exploring CAR therapies. In July 2014, the anti-CD19 CAR therapy CTL019, which is manufactured through an agreement between Novartis and the University of Pennsylvania, received a breakthrough therapy designation from the FDA for pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia.
Capitalizing on the excitement, another company investigating CAR-modified therapies, Juno Therapeutics, mounted one of the largest biotech startups in recent history, by generating over $300 million in investments within a year. This company has unique partnerships Fred Hutchinson Cancer Research Center, Memorial Sloan Kettering Cancer Center, and Seattle Children’s Research Institute.