JCAR014 is a chimeric antigen receptor (CAR) T-cell therapy developed by Juno Therapeutics to treat non-Hodgkin’s lymphoma.

How JCAR014 works

Non-Hodgkin’s lymphoma consists of a group of closely related blood cancers that are caused by the abnormal behavior and fast growth of immune cells.

JCAR014 is a therapy that uses the patient’s own immune cells to fight the cancer cells. In particular, the therapy enlists T-cells, a type of immune cell that can identify and destroy abnormal or infected cells. Juno’s CAR-T technology acts to reprogram these T-cells to target cells that express a specific protein, called CD19, that is commonly found on the surface of cancerous cells.

T-cells are first extracted from the patient’s blood sample and are genetically modified to produce a CAR protein. The CAR consists of an antibody, a protein that will interact with CD19 to stimulate a signaling domain, sending a message to the T-cell when CD19 binds to it.

Before the modified T-cells are returned to the body, patients are given a form of chemotherapy called lymphocyte depletion. This creates a better environment for the modified T-cells to expand and persist in the body. JCAR014 is administered as an intravenous infusion, and should then track down and destroy the cancer cells.

JCAR014 aims to provide modified cytotoxic, or “killer,” T-cells in a 1:1 ratio with modified helper T-cells, which help activate the killer T-cells. This should increase the efficiency of the treatment, and reduce the adverse effects seen in other CAR-T based therapies.

JCAR014 in clinical trials

The results of an early-phase study of JCAR014 carried out by the Fred Hutchinson Cancer Research Center have been published in the journal Science Translational Medicine. The paper described the safety and efficacy of different doses of JCAR014 in 32 advanced, B-cell non-Hodgkin’s lymphoma patients after receiving lymphodepletion chemotherapy with either just Cytoxan (cyclophosphamide) or in combination with Fludara (fludarabine) .

The results demonstrated that an intermediate JCAR014 dose combined with both Cytoxan/Fludara (Cy/Flu) chemotherapy appeared to be the most effective and safe, with an overall response rate of 82 percent. Out of the 11 patients given this regime, seven showed a complete response (64 percent of all patients), where no signs of cancer were present for a time. This is markedly higher than in the Cytoxin-only group, where only 8 percent of patients achieved a complete response.

The safety profile was promising in the treatment group receiving intermediate JCAR014 with Cy/Flu, as common adverse effects associated with other CAR-T therapies, such as cytokine release syndrome and severe neurotoxicity, were only seen in one and two patients, respectively.

The Fred Hutchinson Cancer Research Center is now recruiting participants for a Phase 1b trial (NCT02706405) of JCAR014 in combination with Imfinzi (durvalumab), in collaboration with Juno, AstraZeneca (and its subsidiary MedImmune), and the National Cancer Institute. The trial aims to enroll 42 patients with B-cell non-Hodgkin’s lymphoma whose cancer has returned following standard treatment.

The trial will assess whether JCAR014 and Imfinzi are safe in combination and have a significant clinical benefit for the patients. It has two treatment arms; in the first, patients will receive JCAR014 on day 0 followed by Imfinzi on day 28, then every four weeks. This will also be followed in the second arm, but an additional dose of Imfinzi will be given immediately prior to JCAR014 (on day -1). Patients will also receive Cy/Flu chemotherapy prior to JCAR014 treatment. The estimated primary completion date of the trial is December 2019.

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