Mayo Clinic researchers are studying a new class of immunotherapy drugs called "bispecific antibodies" that have demonstrated potent tumor-killing activity in multiple myeloma. A paper highlighting this work was published in Blood Cancer Discovery.

"CAR-T (chimeric antigen receptor-T cell therapy) cell therapy, which uses a patient's own modified immune cells to kill cancerous tumors, is arguably one of the biggest steps forward in treating cancer to date," says Marta Chesi, PhD, a Mayo Clinic cancer researcher.

Dr. Chesi says that while CAR-T cell therapy has proven effective, for unclear reasons, multiple myeloma patients eventually relapse. She says that bispecific antibodies represent a new class of immunotherapy drugs based on similar technology as CAR-T cell therapy, but it uses off-the-shelf small molecules to guide a patient's immune response to kill cancerous tumors rather than the patient's own modified immune cells.

"Our team at Mayo Clinic has developed a unique model to optimize immunotherapy in multiple myeloma in collaboration with the Discovery Biotherapeutics Group at Bristol Myers Squibb," says Dr. Chesi. "We have developed new therapeutic drug combinations with bispecific antibodies that may help prevent resistance and relapse in multiple myeloma."

"The unique model called 'IMiDs,' short for immunomodulatory drugs, are a class of drugs known to stimulate immune cells, so they were an obvious combination to partner with immunotherapy," says Dr. Chesi. She cautions however, that the addition of immunomodulatory drugs to immunotherapy could overactivate and exhaust immune cells, rendering them incapable of killing tumor cells over time. This may lead to excessive toxicity.

"Our research may ultimately lead to the development of new and better forms of immunotherapy," says Dr. Chesi. "For example, we found that the use of an IMiD in combination with immunotherapy brings unwanted toxicities, while only marginally improving efficacy. Instead, the addition of cyclophosphamide, thought to be an immunosuppressive agent, prevents excessive immune activation and helps to promote longevity in immune cells, which prevents tumor reoccurrence."

Dr. Chesi cautions that it is essential for researchers to evaluate immunotherapy in preclinical immunocompetent animal models that predict clinical activity in humans before the treatment is tested in patients. She says the availability of mouse models that are sensitive to immunomodulatory drugs will allow researchers to better understand and predict toxicities, before drugs are tested on patients in clinical trials.