In a keynote presentation at the MedCity CONVERGE conference, medical oncologist Dr. Joshua Brody, the director of the lymphoma immunotherapy program at Icahn School of Medicine at Mount Sinai in New York, talked about some of the hype and hope of CAR-T and checkpoint blockade immunotherapy treatments. Brody also highlighted some of the work his lab is doing, using wry metaphors to make his points.
CAR-T cells vs Checkpoint Inhibitors
Brody noted that with CAR-T cells, clinicians give the immune cells specific instructions of which targets the immune system should go after and how to do it. He contrasted this approach with checkpoint blockade and cancer vaccines, in which oncologists merely facilitate the individual’s immune system to fight cancer. He likened the difference in the two approaches to giving a woman a fish and teaching a woman how to fish.
CAR-T cells 2.0 A crucial part that oncologists changed about using CAR-T cells is to get rid of all or many of the endogenous T cells, so the CAR T cells have no competition, is to carry out homeostatic proliferation and activation, which is critical to the efficacy of CAR-T cells. The treatment for diffuse large B cell lymphoma that doesn’t respond to chemotherapy has been successful in many patients, leading to durable remission.
Checkpoint blockade uses cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1), which Brody likened to brake pedals on a car. Although T cells can attack cancer cells, they can sometimes go after healthy cells as well. He noted that Hodgkin’s lymphoma patients have a 65 percent response rate with this treatment, three times higher than that for lung cancer. On the downside, 8 percent of patients experience high-grade liver toxicity and requires hospitalization.
“Really the take home here is that we are yelling at these immune cells to be free and do what they want,” Brody said. “When you yell at them more and more … that’s just a lot of yelling at these immune cells. If we can cut the brake pedals of the immune automobile and push the gas pedals of the immune automobile… We believe very strongly that we need to guide this automobile a little bit… That way, we could avoid hitting the wrong thing [i.e., healthy cells].”
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
The Benihana of vaccines: In situ vaccine One component of the body’s immune response is antigen-presenting cells — one type of the cells are dendritic cells. One approach to immunotherapy involves injecting dendritic cells directly into tumors using clinical grade FLT3 ligand, a small molecule that can be used to stimulate the growth of dendritic cells. Using toll-like receptor 3, one of the primary activating switches of dendritic cells, Brody described how the process works using one of many metaphors peppered throughout his presentation. “We can get the generals to tell the soldiers, ‘Go after the stuff around here specifically’ [the tumor] and then those soldiers can go systemically and get the job done.” We brought this into an early phase clinical trial based on some preclinical work in the lab.
“We sometimes call this the Benihana of vaccines,” Brody said, because just as the Japanese steakhouse would bring the ingredients for a meal and cook it at the table, the components of the vaccine are prepared on site. He described it as a therapeutic vaccine. He also noted that in the lab, when PD-L1 antibodies are added to the in situ vaccine, the cure rate goes from 40 percent to 90 percent. Brody said his group plans to do a clinical trial, applying the antibodies and in situ vaccine to lymphoma, breast cancer and head and neck cancer.
Dendreon Corp.’s Provenge (sipuleucel-T) is the only FDA-approved cancer vaccine for prostate cancer. Bristol-Myers Squibb’s Opdivo (nivolumab) and Merck & Co.’s Keytruda (pembrolizumab) are approved PD-1 inhibitors, while Bristol’s Yervoy (ipilimumab) is a marketed CTLA-4 inhibitor. Approved PD-L1 inhibitors include Roche’s Tecentriq (atezolizumab), Pfizer and Merck KGaA’s Bavencio (avelumab) and AstraZeneca’s Imfinzi (durvalumab). Novartis’ Kymriah (tisagenlecleucel) and Gilead Sciences’ Yescarta (axicabtagene ciloleucel) are the currently approved CAR-T therapies.
Alaric DeArment contributed to this story.
Photo: Getty Images
