JCAR017 is a chimeric antigen receptor (CAR) T-cell therapy being developed by Juno Therapeutics, in collaboration with Celgene, to possibly treat certain patients with aggressive B-cell non-Hodgkin’s lymphoma (NHL).
How JCAR017 works
NHL consists of a group of closely related blood cancers that are caused by the abnormal behavior and fast growth of immune cells, or lymphocytes. Types of NHL can be broadly split based on the type of lymphocyte the cancer originated in, either T-cells or B-cells.
JCAR017 is a therapy that uses the patient’s own healthy T-cells to fight the cancer. As part of the immune system, T-cells act to identify and destroy abnormal or infected cells. However, cancerous cells often find ways to evade this.
Juno’s CAR-T technology acts to reprogram T-cells to target cells that express a specific protein, called CD19, that is commonly found in cancerous B-cell NHL.
To produce JCAR017, T-cells are first extracted from the patient’s blood and are genetically modified to produce a CAR protein. The CAR consists of an antibody, a protein that interacts with CD19, which can stimulate a signaling domain, sending a message to the T-cell when CD19 binds to it.
Prior to the modified T-cells being returned to the body, patients are given a chemotherapy aiming at lymphocyte depletion. This creates a better environment for the modified T-cells to expand and persist in the body. JCAR017 is administered as an intravenous infusion, and is designed to track down and destroy the cancer cells.
Unlike most CAR-based therapies, JCAR017 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 severity and frequency of adverse effects, such as cytokine release syndrome (CRS), common in other CAR-T based therapies.
JCAR017 in clinical trials
Juno is currently assessing the length of time the modified T-cells stay in the body, as well as the safety and antitumor activity of JCAR017 in a Phase 1 clinical study (NCT02631044) called TRANSEND NHL 001. This study aims to assess the effect of JCAR017 taken on a single or double dose schedule, in an estimated 274 patients with B-cell NHL that has returned or has not responded to standard treatment. Before treatment with JCAR017, patients will receive Cytoxan (cyclophosphamide)/Fludara (fludarabine) lymphodepletion chemotherapy, also called Cy/Flu.
Juno presented an update on the results of the TRANSCEND study at the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO). So far, 71 NHL patients have been treated, including patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL).
So far, data from 55 patients have been analyzed. The overall response rate (ORR) is 76 percent, with 39 percent of patients achieving complete remission (CR), where no symptoms of the cancer are present.
Of the “core” group, consisting of 44 patients who will take part in an upcoming JCAR017 trial in later 2017, the response was very positive. The ORR was 85 percent (38/44 patients), with 59 percent (26/44) in complete remission. Preliminary data suggest that the response may be slightly improved with a higher dose of JCAR017, with no increase in toxicity reported so far.
The safety profile so far is also positive. No deaths relating to treatment have been reported, and 66 percent of the core group reported not experiencing any symptoms of CRS or neurotoxicity. One patient (2 percent of all patients) in the core group experienced severe CRS and eight (18 percent) experienced severe neurotoxicity.
In December 2016, JCAR017 was designed a breakthrough therapy by the U.S. Food and Drug Administration (FDA) for relapse/refractory diffuse large B-cell NHL.
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