Day 4 of the annual meeting of the American Association for Cancer Research (AACR) seemed to be all about adoptive cell therapy. In this approach, immune cells from a patient are removed from the body, altered or expanded in the lab, and then re-infused into the patient. Various approaches are being explored, with the most celebrated being chimeric antigen receptor (CAR) T cell therapy.
CARs are hybrid molecules made up of the antigen-binding region of an antibody joined to the signaling region of a T cell receptor. They unite what is best about each molecule—the binding power of an antibody and the killing ability of a T cell.
Various laboratories from institutions such as the University of Pennsylvania, Memorial Sloan Kettering, Fred Hutchinson, and the National Cancer Institute have used CARs against acute lymphoblastic leukemia (ALL), achieving remarkable response rates. Around 90% of a small but growing group of patients treated this way have experienced complete remissions, including 8-year-old Emily Whitehead, treated at Penn in 2012.
To date, most CARs in use have targeted an antigen called CD19, found on all B cells in the body, including the B cells from which leukemia cells are derived. CD19 is in some sense a perfect target for CAR therapy because all CD19-bearing cells—both normal and cancerous—can be eliminated from the body without threatening life, provided a patient receives supplemental immunoglobulin therapy. The same cannot be said for other antigens in the body. Current research in the field is directed to identifying other antigens that might serve as effective targets for CAR T cells.
Carl June, M.D., who is a professor at the University of Pennsylvania and also a member of CRI’s Scientific Advisory Council, addressed this topic today in a talk called, “CAR T Cells: Can we move beyond B cells?” June is the recipient of the third annual AACR-CRI Lloyd J. Old Award, named after the late pioneer of cancer immunotherapy who was also CRI’s medical director for 40 years. This talk was the award lecture. After tracing the history of this important technology, June gave an example of how CAR T cells might be successfully targeted against antigens other than CD19. The brain cancer called glioblastoma multiforme (GBM) is associated with an altered version of the epidermal growth factor receptor, dubbed EGFRviii. June’s lab developed CAR T cells that can specifically recognize and kill cells bearing EGFRviii, but leave normal EGFR-bearing cells alone. A phase I trial is currently enrolling patients. Earlier in the day, June discussed a trial using CD19-targeting CARs against multiple myeloma. While multiple myeloma cells do not themselves express CD19, they originate from B cells that do. Early results from a pilot study indicate that CAR therapy may be highly effective in this cancer type as well.
Another investigator who has been leading the CAR T cell charge is Michel Sadelain, M.D., Ph.D., of MSKCC, who is also a member of CRI’s clinical trial network. In his talk today, Sadelain discussed strategies that he and members of his lab are using to construct “next generation” CARs. The CARs that have been used so far to treat leukemia are what’s known as “second generation” CARs. Advances in our understanding of the biology of T cell activation have made it possible to construct third-generation CARs with an even greater capacity to multiply and persist in patients—two qualities associated with stronger and more durable responses in patients. The first batch of these third generation CARs from Sadelain’s lab are targeted to a molecule called mesothelin, which is overexpressed on numerous cancers such as pancreatic cancer and mesothelioma, but rare on normal tissues. These new cells will be tested in a phase I trial for patients with triple-negative breast cancer (TNBC), mesothelioma, and non-small cell lung cancer who also have metastases to the pleura—the lining surrounding the lungs. In this trial, the CAR T cells will be administered directly into the pleural space, rather than intravenously, because preclinical studies done in mice suggest that this approach is more effective. This trial is supported by the CRI-SU2C Dream Team grant.
Philip Greenberg, M.D., of the Fred Hutchinson Cancer Center, who is also a member of CRI’s Scientific Advisory Council, presented work on engineering T cells to target a molecule called WT1, which is found in 90% of patients with leukemia but rarely found in patients without cancer. His lab has also genetically engineered T cells to recognize mesothelin.
“Rather than focus on the cancer cells, we can use drugs to target the T cells to make them better cancer killers.” —Nicholas Restifo, M.D.
Part of the motivation for synthesizing more advanced CARs is the fact that T cells need a variety of signals to become fully active. CARs are made in such a way that many of these signaling molecules are “built in” to the receptor. But there is a limit to how self-sufficient you can really make a CAR T cell. Malcolm Brenner, M.D., Ph.D, of Baylor College of Medicine, has attacked this problem from a different angle. He has been exploring how virus-specific T cells—ones trained to kill viruses—can be enlisted in the fight against cancer. Because several types of cancer are caused by viruses, it is possible to engineer T cells with receptors against these viruses to kill the associated cancer. But he has also found that virus-specific T cells can be combined with CARs to create a powerful weapon against non-virally caused cancers. By equipping a virus-specific T cell with a CAR targeting a cancer antigen, it is possible to use the costimulation that comes from the virus as a way to jumpstart the CAR in its fight against cancer. In this approach, patients are first vaccinated with virus and then given the CARs. Late-stage clinical trials of this technique are currently under way.
While CARs stole the show today, a second focus of day 4 was on combining targeted therapies with immunotherapies to maximize benefits for patients. CRI scientists Antoni Ribas, M.D., Ph.D., of UCLA, and Jedd D. Wolchok, M.D., Ph.D., of Memorial Sloan Kettering, as well as Jennifer Wargo, M.D., of MD Anderson Cancer Center, all presented work documenting both the promise and the risks of combining BRAF inhibitors with checkpoint blockade therapy. While some BRAF inhibitors appear to complement the action of checkpoint inhibitors in a way that is helpful to patients, others appear to cause excess toxicity. Determining the precise timing and sequence for how to combine these agents for effective therapy remains a pressing task.
Nicholas Restifo, M.D., of the National Cancer Institute, rounded out the theme of combinations by suggesting ways that targeted agents—in this case ones directed at controlling T cell differentiation—might be effectively combined with adoptive T cell therapy. “Rather than focus on the cancer cells,” he said, “we can use drugs to target the T cells to make them better cancer killers.”
Check back tomorrow for updates from the final day of the AACR meeting.