Shipra Ghandi, MD
Encouraging results from a phase 1 clinical trial conducted at Roswell Park Comprehensive Cancer Center between 2019-2020 have laid the foundation for a phase 1/2a study for patients with metastatic or unresectable triple negative breast cancer (mTNBC).
The initial study revealed that a short-term systemic chemokine modulating regimen (CKM) “primed” the immune system before the introduction of the immune checkpoint inhibitor pembrolizumab (brand name Keytruda). The full results, reported in The Journal for ImmunoTherapy of Cancer last year, showed that while median survival for metastatic mTNBC is just 17.2 months — worse than any other breast cancer subtype — half of the study’s eight participants were still alive at data cutoff in January 2023. Two of the four had stable disease at the time of reporting, while another survived more than four years with no evidence of disease.
Biopsies taken before and immediately after CKM revealed that CKM appears to direct immune cells to cancer cells, maximizing the effectiveness of pembrolizumab, which interferes with cancer cells’ ability to grow and spread. The treatment regimen led to increased markers of cytotoxic T lymphocytes and their activity, with a more than tenfold average rise in CD8+ T cells, which help the immune system work more effectively, and a more than 300-fold increase in the CD8+/FoxP3 ratio, a predictor of disease-free survival in many types of cancer.
Like the phase 1 trial, the current study, “Rintatolimod, Celecoxib and Interferon Alpha 2b with Pembrolizumab for the Treatment of Patients with Metastatic or Unresectable Triple Negative Breast Cancer” (NCT0576166), will be overseen by Principal Investigator Shipra Gandhi, MD, Associate Professor of Oncology, Department of Medicine, with the scientific leadership of Pawel Kalinski, MD, PhD, Chair of Immunology and Senior Vice President for Team Science.
The non-randomized study is open to patients with metastatic or unresectable mTNBC who have no other curative treatment options. It aims to enroll 12 patients, who will be assigned to one of two cohorts. Both cohorts will receive the same combination therapy, but on different schedules: a chemokine modulation therapy (CKM) of rintatolimod (brand name Ampligen), celecoxib (brand name Celebrex) and interferon Alpha 2b (brand name Intron A), plus pembrolizumab. Rintatolimod and interferon alpha 2b modify the immune response and tumor-related processes such as tumor cell growth, blood vessel growth and metastasis. Celecoxib, an anti-inflammatory, can cause cell death and may inhibit angiogenesis.
All patients will receive CKM on days 0, 1, 2, 7, 8 and 9. However, pembrolizumab will be administered to the first cohort on Day 9 and then every three weeks afterward for up to four doses, while the second cohort will receive it on Day 2 and then every three weeks beginning in the fourth week.
The study’s primary objective is to evaluate the safety of the regimen. Secondarily, it will compare its efficacy to historic use of pembrolizumab and other anti-PD1/PD-L1 therapies alone, as determine by progression-free survival, overall survival, overall response rate and disease control rate.
“Our findings showing that CKM can modulate the tumor microenvironment are intriguing,” says Dr. Gandhi. “We expect that this study, and others in the future, will enable us to better understand and improve responses to checkpoint inhibitors in patients with this notoriously difficult-to-treat form of breast cancer.”
Metastatic triple negative breast cancer accounts for 10-15% of all breast cancers.
BROADCASTMED