CAR-T Gene Therapy Clinical Trials - Success Story and Beyond

Recently, two CAR-T (Chimeric Antigen Receptor T cell) gene therapies were approved by FDA. The first one is tisagenlecleucel manufactured by Novartis and is indicated for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL). The second one is axicabtagene ciloleucel by Kite pharmaceutical (now part of Gilead) and it is indicated for treating adult patients with certain types of large B-cell lymphoma or certain types of non-Hodgkin lymphoma (NHL).who have not responded to or who have relapsed after at least two other kinds of treatment.

Before the approval of tisagenlecleucel, FDA summoned an advisory committee meeting for the safety concerns on July 12, 2017. The official approval came one and half months after advisory committee votes unanimously in favor of the approval.

The second CAR-T product approval came just one and half months after the first CAR-T approval and did not need to go through the advisory committee meeting process.

From the clinical trial design standpoint, both approvals were based on a pivotal study with relatively small, but sufficient sample size. Since the study was a single-arm with no control group, the results were compared with the historical control (or a commonly accepted criteria).

For Novartis’ tisagenlecleucel, the pivotal study is registered on clinicaltrials.gov as “A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell Acute Lymphoblastic Leukemia”. The briefing book of the advisory committee meeting detailed the background information of the CART, the study design, and the results.

The primary efficacy endpoint is the overall remission rate (ORR) during the 3 months after tisagenlecleucel administration; ORR includes complete remission (CR) and complete remission with incomplete hematologic recovery (CRi), as determined by independent review committee (IRC) assessment.

The pre-specified primary efficacy endpoint tested the null hypothesis of the ORR being less than or equal to 20% against the alternative hypothesis that the ORR was greater than 20% at an overall one-sided 2.5% level of significance. The study met its primary objective if the lower bound of the 2-sided 95% exact Clopper Pearson confidence intervals (CI) for ORR was greater than 20% (note: I wrote an article about Clopper Pearson confidence interval).

The study results showed the remarkable results. ORR is 82.5% (52/63). The lower bound of the 95% exact confidence interval using Clopper Pearson method is 70.9% - way above the pre-specified criterion of 20%.

The approval of Kite’s axicabtagene ciloleucel was based on a similar study design. In clinicaltrials.gov, the study was registered as “A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 in Subjects With Refractory Aggressive Non-Hodgkin Lymphoma (NHL)” – so called ‘ZUMA-1’ trial. The primary efficacy endpoint is ORR (Objective response rate) consisting of complete response [CR] plus partial response [PR] per the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma.

The study results was announced in Kite’s press release. The results indicated that the ORR is 82% (83/101) – p value is less than 0.0001.  The 95% exact confidence interval for ORR was not provided, but with Clopper Pearson method, we can calculate the lower bound of the 95% confidence interval to be 73% - it is probably way above the pre-specified ORR (historical control if exist) for patients without CAR-T treatment. 

While we are excited about the advances in gene therapy, the long-term safety should still be followed. Both approved products carry the black box and the short term safety issue (could be life-threatening) is mainly the cytokine release syndrome (CRS).

It will be interesting to see how the cost of these CAR-T therapy will be managed and accepted by the community. The Novartis tisagenlecleucel (brand name Kymriah) is priced at $475,000 for a treatment course. Kite’s axicabtagene ciloleucel (brand name Yescarta) is priced at $373,000 for a treatment course.

The development of therapies like CAR-T requires great collaboration between the industry and the academic and government. The Novartis’s tisagenlecleucel was mainly developed by the University of Pennsylvania. Kite’s axicabtagene ciloleucel was developed by the National Cancer Institute.

There is an article in New England Journal of Medicine by Dr. Rosenbaum “Tragedy, Perseverance, and Chance — The Story of CAR-T Therapy”.

CAR-T is now very popular in China. A lot of investigational clinical trials using CAR-T therapy are ongoing in China. Someone did a search in clinicaltrials.gov and found more CAR-T clinical trials in China than US.

Both CAR-T successes are hematologic cancers, the next challenge will be to find the successful CAR-T therapy in solid tumors.

The success in CAR-T should bring us a hope that someday we can transplant the pig organs into human - an area my company is a pioneer. See the article in New York Time "Gene Editing Spurs Hope for Transplanting Pig Organs Into Humans".