Fighting Cancer With Killer T-Cells

Three companies are locked in a tight race to develop next-generation immuno-oncology treatments called chimeric antigen receptor T-cells (CARTs)sophisticated, personalized medicines that use patients’ own cells to destroy their tumors: Juno Therapeutics, Novartis and Kite Pharma. All three companies continue to report progress for CART therapies in treating blood cancers like leukemia and lymphoma. These treatments work by targeting a specific antigen, or protein, on the surface of cancer cells called CD19. T-cells are extracted from the blood of patients then re-engineered to home in on cancer cells bearing the antigen and kill them. The advantage of CD19 is that it’s widely prevalent in blood-borne cancer cells but not on normal tissues, making CARTs extremely precise weapons. Kite, Novartis and Juno have all told investors that if the trials stay on track, they could see their most advanced CARTs approved by the FDA as early as 2017. But will the engineered T-cell approach translate to other types of cancers? Could targeting antigens aside from CD19 make it possible to greatly expand the use of these cells and finally conquer previously unbeatable tumors? Data released not only from the companies working in this field, but also from independent academic researchers reporting on early discoveries—offers an early window into what might be possible. CD19 isn’t the only antigen that can be targeted with T-cells. Ever since the first generation of CARTs started showing promise—most notably in 2014, when 27 out of 30 young patients with leukemia had complete remissions in a trial of Novartis’ CTL019—scientists all over the world have been searching for different antigens that may widen the potential patient pool for the CART approach. One popular target is CD22, which is also prevalent in blood cancers. In early trials of the original CD19-targeting CARTs, some patients relapsed with cancers that no longer produced CD19 but did have CD22. In trials discussed at AACR of Juno’s CD22 CART, JCAR018, three patients with B-cell acute lymphoblastic leukemia (ALL) remain in remission. Complete remissions have been seen both in patients who hadn’t received CARTs before and in those who relapsed after being treated with CD19-targeting CARTs. “What may be even more interesting is using a CD19 and a CD22 CART together, because that increases the potential for even higher levels of durable remissions,” Bishop says. “That’s not in the clinic yet, but that’s a potential next step.” WT1, an antigen that appears in early studies to offer a way for engineered T-cells to attack acute myeloid leukemia (AML), mesothelioma and possibly other cancers. This technology is an improvement because T-cell receptors (TCRs), differ from CARTs because they are not “chimeric” (or containing genes that don’t naturally occur in people) but rather fully human, which may make them less likely to touch off dangerous immune responses. TCRs can also target proteins that are not just on the surface but actually inside of cancer cells, which may make them applicable to a wide range of cancers.Researchers from the University of Pennsylvania and Harvard reported that T-cells that target a tumor-specific protein known as EGFRvIII were able to cross the blood-brain barrier and target glioblastoma tumors. About 30% of glioblastoma patients have EGFRvIII-positive tumors, and this small trial in nine patients, which was sponsored by Novartis, showed that T-cells targeting this antigen seem safe. T-cells that can attack pancreatic cancer may be on the horizon, too.Pancreatic cancer is notoriously difficult to treat, and many consider it to be a hard target for engineered T-cells because it doesn’t produce many unique proteins for the cells to attack. Scientists have engineered T-cells that target mesothelin, a protein that’s over-produced in the majority of pancreatic tumors. Mesothelin is also present in normal cells, however, raising concerns that engineered T-cells that target it could be too toxic. The Fred Hutch scientists were encouraged by animal trials, which showed that the T-cells they developed stayed only briefly in those normal tissues—which include the linings of the heart and lungs—and didn’t harm them, moving along quickly to the tumor cells. They plan to start human trials by the end of the year. Targeting CD19 is showing promise in other blood cancers. While Juno’s and Novartis’ most advanced CART programs are for patients with ALL, Kite has been making progress against another tough-to-treat blood cancer, non-Hodgkin lymphoma (NHL). In December, Kite announced that its CART, KTE-C19, produced four complete remissions in a Phase I study of seven patients with NHL. At the AACR conference, the company updated the results, saying that three of the patients had an ongoing complete response to the therapy ranging from six to nine months. The company is on track to file for FDA approval by the end of this year.

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