It is well established that CD38-targeting monoclonal antibodies daratumumab and isatuximab kill multiple myeloma cells, both directly and by recruiting tumor-destroying immune cells, a process known as antibody-dependent cellular cytotoxicity (ADCC).1 But it is less clear what happens next — does the killing of tumor cells release proteins and other materials into the environment that elicit additional immune responses—a phenomemom that has been called dubbed “in vivo vaccination”? And if so, does this “vaccination” lead to improved clinical responses in patients with multiple myeloma?
A small study of 4 patients who received isatuximab for relapsed or refractory multiple myeloma (RRMM) found that 2 of these patients had antibody responses against certain myeloma-associated antigens and a T-cell response against CD38 in the weeks following treatment. These same 2 patients went on to have a complete remission. The other 2 patients did not elicit detectable immune responses and did not have clinical responses.
“We think we observed an in vivo vaccination effect in the patients and this seems to correlate with clinical responses,” Djordje Atanackovic, MD, an associate professor at the University of Huntsman Cancer Institute, Salt Lake City, Utah, told Cancer Therapy Advisor. Dr Atanackovic is the lead author of the study, which was published in Leukemia.2
“The most important question now that we have identified this mechanism is, is it just a correlation or is it … responsible for the clinical effects that we see?” Dr Atanackovic said. He hopes that an ongoing clinical trial will confirm this correlation and help explain whether the immune response is clinically important (ClinicalTrials.gov Identifier: NCT03194867).
The study additionally found that the 2 patients who had both an immune response and a clinical response also had antibodies against several myeloma antigens before starting isatuximab. This finding raises the possibility that myeloma-associated antibodies could one day serve as biomarkers for predicting which patients will benefit from isatuximab. Such antibodies could potentially also be predictive biomarkers for response to daratumumab, added Dr Atanackovic.
Although isatuximab is under investigation by the Food and Drug Administration (FDA), daratumumab (Darzalex®) is FDA-approved as a single agent and in combination with lenalidomide, bortezomib, or pomalidomide for patients with RRMM, and in combination with other agents for patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant.
Currently, the global standard of practice is that clinicians look for the presence of CD38, along with CD138 and about a dozen other markers, in samples from patients with RRMM, C. Ola Landgren, MD, PhD, professor of medicine and chief attending physician of the myeloma service at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, told Cancer Therapy Advisor. However these tests do not really help clinicians determine who should receive daratumumab, added Dr Landren, who was not involved in the current study. (The vast majority of patients with multiple myeloma are positive for CD38, and many of them do not respond to daratumumab.)
“If this study were true, if this were to be expanded in a larger cohort [of 50 to 100 patients], and you really truly show this is highly predictive, you could now start thinking of, ‘Could this play a role in decision making?’” Dr Landgren said. To date, research has mostly focused on the immune responses following treatment with daratumumab rather than isatuximab, he noted.