Mechanisms of Response and Resistance to DLL3-Targeted T Cell Engager Therapy

Principal Investigators: Himisha Beltran, MD (Dana-Farber Cancer Institute)

Co-Investigators: Andres Acosta, MD (Brigham and Women’s Hospital), Jacob Sands, MD (Dana Farber Cancer Institute), Sheng-Yu Ku, PhD (Dana-Farber Cancer Institute)

Description:

• Neuroendocrine prostate cancer (NEPC) is a rapidly progressive and highly lethal form of advanced prostate cancer. There are no approved therapies for NEPC and very few clinical trials have been dedicated to patients with NEPC.
• Beltran and colleagues have been studying NEPC biology to discover therapeutic targets and develop new treatments.
• Her team identified DLL3 as a protein that is on the surface of the vast majority of NEPC tumor cells and other neuroendocrine cancers such as small cell lung cancer (SCLC) but is not expressed in normal cells. The cancer specificity and optimal cellular location of DLL3 make it a promising therapeutic target for these difficult to treat cancers.
• Beltran and colleagues have observed promising preliminary safety and efficacy with the novel DLL3-targeting immunotherapy, HPN328, in a phase 1 trial in NEPC and SCLC. HPN328 is a tri-specific T cell engager, that simultaneously binds to DLL3 on tumor cells and to T cells, thereby bringing T cells into contact with tumor cells to kill them (its 3^rd arm binds to albumin in blood, which increases its circulation time).
• In this project, the team will develop methods to improve patient selection for DLL3-targeted therapies, using samples and data from patients on the phase 2 expansion trial. DLL3 levels, immune cells, and tumor gene expression and mutations will be evaluated in NEPC and SCLC patient tumor and blood samples, before and during HPN328 treatment, to identify patterns that correlate with treatment responses.
• Mouse models will be studied to understand the mechanism of action of HPN328 and potential treatment resistance mechanisms. Mouse models of NEPC and SCLC will be treated with HPN328.  The effects of differences in DLL3 expression, T cell activity, and tumor microenvironment, on treatment efficacy will be studied. Whether combining HPN328 with other immunotherapies may increase efficacy will also be investigated.
• If successful, this project will identify biomarkers for selecting NEPC and SCLC patients most likely to benefit from DLL3-targeting treatments and identify strategies for improving the efficacy of HPN328.
• The direct comparison of NEPC with SCLC will reveal biological similarities between these cancer types and enable knowledge from one field to be applied to the other, ultimately improving outcomes for patients with these aggressive cancers.

What this means to patients:  NEPC is a highly aggressive and lethal form of advanced prostate cancer with no approved therapies. Dr. Beltran and team are investigating a new immunotherapy for NEPC that may also have efficacy in SCLC. They will determine how to best select patients for this treatment and identify strategies to improve treatment efficacy.