There’s no question that immuno-oncology is one of, if not the hottest fields in pharma today. PD-1 inhibitors have emerged as transformative treatments for some solid tumor indications and we have witnessed a meteoric rise in clinical studies of immune checkpoint inhibitors across a broad spectrum of oncology indications. But what lies beyond immune checkpoint inhibitors? There is a frenzy of R&D activity that is uncovering alternative ways of manipulating the immune system; one approach is chimeric antigen receptor (CAR) T-cells. CAR T-cell therapy is an exciting and rapidly growing field that involves extracting a patient’s own T cells, expanding and modifying them ex vivo to recognize tumor associated antigens, before transferring back to the patient. Unlike in 2015, there have been no major revelations for key CAR-T players—Novartis, Juno Therapeutics, Kite Pharma—at this year’s ASCO, but the flurry of data updates is indicative of progress in this hot field.

Juno and Kite are racing to produce clinical data and aiming to reach the market in 2017. Juno’s lead CD19-targeted CAR T-cell therapy, JCAR015, is in Phase II (ROCKET) trial for acute lymphoblastic leukemia (ALL). Kite aims to file for U.S. FDA approval of its lead therapy, KTE-C19, for diffuse large B-cell lymphoma (DLBCL) before the end of 2016.  Juno and Kite report the following pipeline updates at the 2016 ASCO meeting:

  • JCAR015: In a Phase I study, 77% of relapsed/refractory (R/R) adult ALL patients (n = 31) achieved a complete response (CR) or remission; CR in patients with minimal disease (n = 20) was 90%. Severe cytokine release syndrome (CRS) occurred in 27% of patients.
  • JCAR014 and JCAR017: JCAR014 achieved durable responses in patients with B-cell malignancies including ALL (n = 36), Non-Hodgkin’s lymphoma (NHL) (n = 41), and chronic lymphocytic leukemia (CLL) (n = 13). CRs in ALL, NHL, and CLL were 94%, 50%, and 45%, respectively. In a Phase I study of pediatric R/R ALL patients (n = 42) treated with JCAR017, CR was 93%.
  • KTE-C19: In a Phase I/II study partnered by the National Cancer Institute (NCI), 47% of DLBCL patients (n = 19) receiving KTE-C19 achieved a CR, all of which are ongoing. CR was also reported in follicular lymphoma (FL) and mantle cell lymphoma (MCL).
  • KTE-C19: In an update to the Phase I of the ZUMA-1 pivotal study, seven refractory DLBCL patients dosed with KTE-C19 achieved a CR of 57%. Responses were ongoing for three patients at nine months follow up. Severe CRS and neurotoxicity was 14% and 57%, respectively.

Novartis has generated the most data to date with its CD19-targeted CAR T-cell therapy, CTL019. The timeline for regulatory submission of Novartis’ CAR T-cell therapy appears more conservative that that proposed by Juno and Kite. Novartis presented the following data at the ASCO meeting:

  • CTL019: With a longer follow up, Phase I data of CTL019 in pediatric R/R ALL (n = 69) showed high and durable CRs (93%); severe CRS occurred in 27%. To improve tolerability, varying dosing and scheduling of CTL019 was assessed in 30 patients. The study finds that a fractioned (split) high dose mitigates CRS without significantly compromising on efficacy.
  • CTL119: Pediatric ALL patients R/R to CTL019 were retreated with CTL019 (n = 3) or CTL119 (n = 4). Sample size is very low, but remission rates appear higher in patients retreated with CTL119. This is the first study of a human CAR T-cell therapy.

CAR T-cell therapy has demonstrated impressive remission rates in ALL and other hematological malignancies, but the jury is still out on the benefit of CAR T-cell therapies. Larger data sets and longer follow ups are needed. How long will patients remain in remission? Will further treatments be needed? Are they practical? Will the benefits outweigh the risks?

What are the key obstacles to reaching market and ensuring uptake?

  • Off-target side effects: CRS can be severe and sometimes fatal. Juno is developing next generation CAR T-cells with built in “suicide switches” as a safety control mechanism and “armored” CAR T-cells to mitigate side effects. Bellicum is developing similar approaches. If side effects are not addressed, Decision Resources Group expects that CAR T-cell therapy will be reserved as a last resort treatment, constraining commercial potential.
  • Complexity and cost of manufacture: The ability to scale-up manufacture of patient-specific (autologous) CAR T-cell therapy to ensure broad access and economic sustainability could pose the biggest challenge. To overcome the limitations of patient-derived therapies, Cellectis is developing “gene-edited” CAR T-cells from healthy donor T cells (allogenic. These products are “off-the-shelf”; production is therefore more easily scaled and standardized.
  • Limited validation in solid tumors: Early clinical success has been restricted to hematological malignancies, limited by the fact they target CD19 expressed in >95% of all precursor B-cells. There are simply few unique solid tumor targets for antibody recognition and this represents a major obstacle in progress.

Despite these obstacles, we could see CAR-T cell therapies enter the market in 2017. It’s too soon (and too close) to call, but Juno and Kite are edging ahead of their competitors and appear to be neck-and-neck in getting commercial manufacturing plants up and running. Juno, Kite, and Novartis’ lead CAR-T cell candidates hold FDA breakthrough therapy designation (BTD) status and Kite’s KTE-C19 has been granted access to the EMA Committee for Medicinal Products for Human Use (CHMP)’s new Priority Medicine’s (PRIME) regulatory initiative. While such designations will not guarantee regulatory approval, they should encourage early dialog with regulatory authorities at key development milestones and expedite drug review processes.

This first wave of CAR T-cell therapies may not be the “best” in this rapidly evolving field, and the greatest advance might come when the potential of CAR T-cells in solid tumors is unlocked, but first regulatory approvals of CAR T-cells would be an exciting milestone. Watch this space with Decision Resources Group. See our content on upcoming offerings on the ALL Disease Landscape & Forecast and upcoming update to the NHL and CLL Disease Landscape & Forecast

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