Study Reveals Why Immuno-Oncology Treatments Are Effective in Only a Minority of Patients

A system-wide immune response, not just a local response limited to the tumor, is what determines successful remission following cancer immunotherapy, according to a new study published in the journal Cell.

The authors of the study developed a genetically engineered mouse model of triple-negative breast cancer to perform a systemic study of an immune response following immunotherapy. The authors studied the immune response to a programmed death-1 (PD-1) inhibitor (known to be ineffective in the mouse model) and compared it with the response to an experimental therapy that the mice are known to respond to. The experimental treatment uses a tumor-binding antibody that binds the tumor and also evokes a dendritic cell response.

Immune cells from several tissues were evaluated and single-cell analysis performed using mass cytometry to quantitate the number and functional status of the immune cells. The analysis found that the anti—PD-1 treatment only triggered a short-term response that was restricted to the tumor, which was in contrast to the system-wide response observed with the experimental therapy that was evaluated. The new treatment triggered a coordinated immune response across many different tissues—sustained activation of peripheral immune cells—even after the response within the tumor died down.

According to lead author Matthew Spitzer, PhD, a member of the Parker Institute for Cancer Immunotherapy, University of California at San Francisco (UCSF), this result suggests that monitoring the immune response within the tumor may not be appropriate endpoint to follow. “You need to see an immune response outside of the tumor to have an effective treatment,” Spitzer said in a statement.

Another important finding from the study was the role played by CD4+ T cells in retaining immune memory—the authors believe that these cells are responsible for a long-lasting immunity to cancer throughout the body. To test this hypothesis, the researchers transplanted CD4+ T cells from successfully treated mice into other mice and found that these activated T cells triggered an immune response against tumors in the transplanted mice.

Although the authors were surprised with the impact of CD4+ T cells—since CD8+ T cells are thought to play a more important role in recognizing dangerous foreign cells in the body—they believe that the important role of CD4+ T cells in other settings also means that they can coordinate an immune response against tumors. More importantly, the results of the mouse model were replicated in patient samples. A similar CD4+ T cell activation signature was observed in the blood of patients who had responded well to treatment with a PD-1 inhibitor for their melanoma, which confirmed the hypothesis of the importance of a system-wide immune response in ensuring a sustained treatment response.

“We simply haven't had a good way to assess immune health across the whole organism until now. We've been looking through a pinhole—now we have an opportunity to see the entire landscape,” Spitzer said.

The work is a collaboration between researchers at UCSF and Stanford University.

Reference

Spitzer MH, Carmi Y, Reticker-Flynn NE, Kwek SS, et al. Systemic immunity is required for effective cancer immunotherapy [published online January 19, 2017]. Cell. pii: S0092-8674(16)31738-X. doi: 10.1016/j.cell.2016.12.022.