A new preclinical study suggests that treating people who have aggressive cancers with immune checkpoint inhibitors, quickly followed with mutation-targeted therapy, can help overcome treatment resistance, a common problem with these types of malignancies.
“We already have powerful drugs in our arsenal against advanced cancers,” said co-senior author Roger S. Lo, M.D., Ph.D., a professor of medicine at the David Geffen School of Medicine at UCLA and member of the UCLA Jonsson Comprehensive Cancer Center. “Knowing how to rationally dose, sequence, and combine them offers physicians realistic and near-term chances to improve patient survival.”
The study tested different sequential-combinatorial regimens in multiple animal models of human melanoma, pancreatic, and colorectal cancers driven by common mutations in genes such as BRAF, NF1, NRAS, and KRAS. It is published today in Cancer Cell, 10.1016/j.ccell.2021.07.023.
Recent studies suggest that combining immune checkpoint inhibitors targeting PD-1/L1 with MAPK-targeted therapy—drugs typically used separately— may help overcome cancer treatment resistance. In their new work, the UCLA team found that simply initiating the therapies together is not optimal. Instead, starting with two doses of anti-PD-1/L1 therapy, then adding MAPK-targeted therapy, was much more effective in prolonging tumor shrinkage and preventing resistance development.
They found one regimen that out-performed the rest. The team also uncovered molecular and cellular mechanisms to explain why sequential administration on top of combination maximizes treatment efficacy. Analysis of their clinical trial data showed that patients who received immune checkpoint therapies, compared to those who had not, responded better subsequently to MAPK-targeted therapy.
“The optimal regimen led to the highest level of both the ‘good macrophages’ in the tumor and the clonal expansion of T cells responsible for killing the tumor,” said co-senior author Gatien Moriceau, PhD, assistant adjunct professor at UCLA’s David Geffen School of Medicine. “Retrospective analysis of clinical data supports our finding, but we need to prospectively test our proposed rapid-fire regimen in clinical trials designed specifically based on our animal studies.”
The team also demonstrated that sequential administration of anti-PD-1/L1 therapy before adding MAPK inhibitors suppresses melanoma brain metastasis and improves the survival of mice. They detected robust T-cell clonal expansion in all body sites the cancer spread to, including the brain. Lead-in with two types of immune checkpoint therapy — anti-PD-1/L1 plus anti-CTLA-4—further eliminated cancer spread, including spread to the brain and prolonged survival in mice.
They explain that with the sequential-combinatorial regimen, they were able to make the tumors more visible to the body’s cancer-fighting T cells and the T cells’ environment more hospitable for their growth and tumor-killing activity.
“In melanoma in particular, we were surprised by how well this regimen suppresses treatment resistance,” Lo said. “In a metastatic model where the majority of animals with metastatic melanoma die within a couple of weeks with brain metastases, the regimen we proposed afforded survival with complete responses that extends routinely to 10 months, which is currently our longest follow-up.”
This study was inspired by observations in the clinic, which generated hypotheses this team tested in the laboratory. Based on these laboratory findings, the team has begun to test this approach in a clinical trial at UCLA.
The lead authors are Yujue Wang, M.D., Ph.D., Sixue Liu, Ph.D., Zhentao Yang, Ph.D., from the David Geffen School of Medicine at UCLA and Alain P. Algazi, M.D., from UCSF.