Juno Accelerates Development of JCAR017, Halts JCAR015

Hans Bishop

Juno therapeutics has shifted its focus toward the development of JCAR017 for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after a series of toxicity-related setbacks culminated in the need to halt the development of JCAR015, according to a statement from the company. Both are CD19-directed CAR T-cell therapies.

In the phase I TRANSCEND trial, JCAR017 demonstrated an objective response rate (ORR) of 80% and a complete response (CR) rate of 60% in patients with relapsed or refractory CD19-positive non-Hodgkin lymphoma (NHL). None of the enrolled patients experienced severe cytokine release syndrome (CRS), although grade 1/2 events did affect 36% of patients. Neurotoxicity impacted 14% of patients and resolved with treatment.

A pivotal trial is expected to begin this year for JCAR017 in DLBCL, the company noted. The agent received a breakthrough therapy designation from the FDA for non-Hodgkin lymphoma in December 2016.

JCAR015 was under exploration in the phase II ROCKET trial for patients with relapsed or refractory B cell acute lymphoblastic leukemia (ALL). This study, which is being halted, was paused in July 2016 and then again in November 2016 following patient deaths that were related to cerebral edema.

“We continue to experience encouraging signs of clinical benefit in our trial addressing NHL, but we also recognize the unfortunate and unexpected toxicity we saw in our trial addressing ALL with JCAR015," Hans Bishop, president and chief executive officer of Juno, said in a statement. "We have decided not to move forward with the ROCKET trial or JCAR015 at this time, even though it generated important learnings for us and the immunotherapy field."

Although JCAR015 and JCAR017 are both directed against CD19, the agents have very different constructs. The cells used to create JCAR015 are composed of CD3+ enriched peripheral blood mononuclear cells, whereas JCAR017 is built using a fixed ratio of CD4+ and CD8+ T-lymphocytes. Each agent is engineered using different viral vectors, namely gamma retroviral for JCAR015 and lentiviral for JCAR017. The binding domain for JCAR015 is SJ25C1 and the costimulatory domain is CD28, whereas JCAR017 has a binding domain of FMC63 and a costimulatory domain of 4-1BB.

Adding to this list of differences, JCAR017 contains an ablative technology to provide better control of proliferation and survival of the engineered T cells, which is not included in JCAR015. This ablative technology, a truncated form of the human epidermal growth factor receptor (EGFRt), allows for rapid killing of the CAR T-cells using cetuximab, if needed. The addition of EGFRt may also have immunostimulating properties.

In addition to NHL, JCAR017 has been explored in a phase I study for pediatric and young adult patients with relapsed/refractory CD19-positive ALL. In this study, the MRD-negative CR rate was 93%. In 14 patients who received preconditioning with fludarabine and cyclophosphamide, the MRD-negative CR rate was 100%. Severe CRS was observed in 23% and grade 3/4 neurotoxicity was also seen in 23% of patients.

In adults with ALL, the CR rate with JCAR015 was 77%. In those with a CR who could be evaluated for MRD, the MRD-negativity rate was 90%. Severe CRS was seen in 27% of patients and 29% of patients had grade ≥3 neurotoxicity.

"We remain committed to developing better treatments for patients battling ALL and believe an approach using our defined cell technology is the best platform to pursue. We intend to begin a trial with a defined cell product candidate in adult ALL next year," said Bishop. "We look forward to sharing detailed data supporting our learnings from the ROCKET trial at an upcoming scientific conference."

In addition to JCAR017 and JCAR015, Juno is also developing JCAR014, which more closely resembles JCAR017 in construct. This agent has shown promise as a treatment for patients with chronic lymphocytic leukemia (CLL), following treatment with ibrutinib. There are plans to study JCAR014 with ibrutinib for CLL, with a study expected to open in 2017. JCAR014 is also being explored with durvalumab for relapsed/refractory non-Hodgkin lymphoma.

Juno has several other agents in their portfolio, including JCAR018, which targets CD22 and JTCR016, a WT-1—targeted T cell receptor therapy. Additionally, the company has CAR T-cell therapies against a variety of other targets for solid tumors, including ROR-1 (JCAR024), MUC-16 with IL-12 secretion (JCAR020), L1-CAM (JCAR023), and a Lewis Y-directed agent.

"Looking forward into 2017, we continue to be optimistic about the progress we are making with JCAR017 and our pipeline more broadly," Bishop said. "We expect 2017 will be a data-rich year of key insights, based on up to 20 ongoing trials by year end, and we plan to present data from these trials as appropriate throughout the year.”

References

1. Abramson JS, Palomba L, Gordon LI, et al. Transcend NHL 001: immunotherapy with the CD19-directed CAR T-cell product JCAR017 results in high complete response rates in relapsed or refractory b-cell non-Hodgkin lymphoma. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 4192.
2. Gardner R, Finney O, Smithers H, et al. CD19CAR T Cell Products of Defined CD4:CD8 Composition and Transgene Expression Show Prolonged Persistence and Durable MRD-Negative Remission in Pediatric and Young Adult B-Cell ALL. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 219.
3. Park JH, Riviere I, Wang X, et al. Impact of disease burden on long-term outcome of 19-28z CAR modified T cells in adult patients with relapsed B-ALL. J Clin Oncol. 2016;34 (suppl; abstr 7003).