A team from Roswell Park Comprehensive Cancer Center is moving a new three-part strategy for treating advanced cancers forward with support from a U.S. Department of Defense (DoD) grant to Pawel Kalinski, MD, PhD, Vice Chair for Translational Research and Rustum Family Professor for Molecular Therapeutics and Translational Research at the Buffalo, N.Y.-based cancer center. The four-year, $6.42 million Breakthrough Award through the DoD's Breast Cancer Research Program will fund a clinical trial in patients with brain-metastatic breast cancer, to be led by Shipra Gandhi, MD, Assistant Professor of Oncology in the Department of Medicine at Roswell Park.
The phase II trial, slated to open in 2020, would be the first clinical study to assess the effectiveness of a three-pronged strategy combining distinct immunotherapy approaches:
- A new dendritic-cell treatment vaccine developed by Dr. Kalinski and colleagues in collaboration with Brian Czerniecki, MD, PhD, Chair of the Breast Oncology Department at Moffitt Cancer Center in Tampa, Florida
- Chemokine modulation using a combination proposed and validated by Dr. Kalinski as an optimized adjuvant for dendritic-cell vaccines, incorporating rintatolimod (brand name Ampligen) and interferon alfa-2b (brand name Intron A)
- Immune checkpoint inhibition
Alone, these therapies are effective for a limited number of patients, but evidence suggests that together they may help break through a persistent challenge in oncology: how to turn "cold" tumors that don't respond to existing therapies into "hot" ones that the immune system can be trained to recognize and pursue.
A major limitation of cancer immunotherapy is that tumors adapt to naturally occurring effector cells by shutting down production of the relevant chemokines in the tumor microenvironment. Our strategy uses a unique combination of biologic agents to make tumors visible to the immune system by making them look like tissue that's been infected by a virus. We've never tested them all together before in patients, but the findings from earlier clinical and preclinical studies lend strong support for assessing this combination even in the most aggressive and hard-to-treat cancer types."
Dr. Pawel Kalinski, overall principal investigator
Three key factors distinguish this platform for combination immunotherapy:
- The approach is tumor-selective, meaning it can act preferentially to generate responses only in cancer tissues, but not in normal, noncancerous tissue
- It selectively activates so-called "good" chemokines in the tumor microenvironment and promotes selective attraction of desirable tumor-fighting immune cells, but avoids activating "bad" chemokines that attract undesirable suppressive cells
- These therapies have been shown in preclinical and clinical trials to be associated with low toxicity and few adverse side effects
The team will study this approach first in patients with localized brain-metastatic breast cancer (BMBC), or breast cancer that has begun to spread to the brain but is not yet widely disseminated. A companion clinical trial in patients with disseminated, leptomeningeal BMBC, to be led by Peter A. Forsyth, MD, Chair of the Neuro-Oncology Department at Moffitt Cancer Center, in collaboration with Dr. Czerniecki, partnering Principal Investigator on the project, will move forward with additional DoD funding of more than $8 million. Both trials will be available to patients at Roswell Park and at Moffitt.
"There are currently no curative treatments for breast cancer that has spread to and grown in the brain, and the options we have often involve significant side effects or harm to healthy tissues. So this is an area of pronounced clinical need," notes Dr. Gandhi, Principal Investigator on the Roswell Park study. "We're particularly encouraged to be developing a strategy that has the potential to be effective for patients with various breast cancer subtypes -; cancers that are positive for HER2 markers as well as notoriously aggressive triple-negative breast cancers."
Roswell Park has three other studies in progress assessing some of the component elements of this new therapeutic platform:
- Celecoxib, Recombinant Interferon Alfa-2b, and Rintatolimod in Treating Patients with Colorectal Cancer Metastatic to the Liver (NCT03403634 – actively recruiting)
- Aspirin and Rintatolimod With or Without Interferon-alpha 2b in Treating Patients with Prostate Cancer Before Surgery (NCT NCT03899987 – authorized by the FDA and Roswell Park's Internal Review Board; not yet recruiting)
- Chemokine Modulation Therapy and Pembrolizumab in Treating Participants with Metastatic Triple-Negative Breast Cancer (NCT NCT03599453 – actively recruiting)
AIM ImmunoTech Inc. has agreed to provide rintatolimod for the new DoD-funded studies in brain-metastatic breast cancer, as well as these ongoing studies.
Dr. Kalinski gratefully acknowledges earlier support for his work through donations to Roswell Park as a critical foundation that allowed him to pursue and attract outside funding for this work.
The new study in patients with BMBC is not yet open to accrual. For information about other clinical trials currently available at Roswell Park, please visit roswellpark.org/clinical-trials, call 1-800-ROSWELL (1-800-767-9355) or contact Roswell Park by email at [email protected]