Combining Radiotherapy and CD47 Blockade to Induce Macrophage-Mediated Abscopal Effects Against Lung Cancer
Abstract
Cancers of the lungs are the second most common newly diagnosed human tumors in men and women, but are the leading cause of cancer-related deaths in both sexes, with over 220,000 cases and 160,000 deaths estimated to occur per year. Management of this disease uses a multimodality treatment approach incorporating surgery, radiation therapy, and chemotherapy. While radiotherapy is a proven method for controlling localized tumors, it is commonly omitted or utilized only for alleviating pain in cases where the cancer has spread to distant sites. Moreover, 35-45% of patients with non-small cell lung cancer (NSCLC) will experience recurrence of disease within the irradiated field within 2 years, while this fraction is even greater for patients bearing the aggressive small cell lung cancer (SCLC) histology. There is therefore a significant need to improve the efficacy of treatments for lung cancer in order to continue to advance towards a cure for patients afflicted with this disease. In recent years, treatments that kill tumor cells through the initiation of a systemic immune response, termed immunotherapies, have shown exciting results for a number of tumor types. Many of these treatments have targeted factors associated with adaptive immune cells known T cells in order to promote their expansion and activity. These treatments have generated interest that, when used in combination with focal radiotherapy, they may cause regression of tumors outside the volume of tissue irradiated, known as the abscopal effect. The ability of radiation to kill tumors beyond the treatment field has been a longstanding goal for radiation oncology; however, this effect has been rare and difficult to reproduce. It is generally believed that the abscopal effect is generated through stimulation of T cells. We sought to determine whether an alternate form of immunotherapy that engages macrophages rather than T cells to kill tumors could synergize with radiotherapy. We focused on agents that inhibit CD47, a don’t eat me signal expressed by tumor cells that prevents them from being engulfed by innate immune cells known as macrophages. Using animal models, we found that combination of a small single dose of radiation with administration of anti-CD47 antibodies could synergistically inhibit the growth of SCLC. Interestingly, we also noted a potent reduction of the growth of unirradiated tumors in animals receiving combination treatment that was not observed for radiotherapy or CD47 inhibition alone. Excitingly, this abscopal effect could be achieved in immunocompromised animals, suggesting that it is mediated by macrophages rather than T cells. These findings encourage further investigation of the generality and mechanism of combination radiation and anti-CD47 treatments to determine what tumor types they may target and how they can be best exploited clinically. This project addresses the LCRP Area of Emphasis, Identify innovative strategies for the treatment of lung cancer. The work proposed here will establish the clinical utility of lung cancer treatment combining radiation and CD47 inhibition. This strategy has a clear path to clinical translation because of radiation is already established as standard of care for this disease, while drugs targeting CD47 are in clinical trials for several tumor types. We are already planning clinical studies to examine the addition of anti-CD47 treatment to lung cancer radiotherapy in order to evaluate our preclinical findings in human patients. Translation of this approach into clinical trials is therefore anticipated in the next 2-4 years pending successful elucidation of the critical clinical factors and mechanism proposed in this project. In addition to this clinical significance, the proposed work will evaluate a novel mechanism for inducing abscopal effects of radiation and will therefore advance our understanding of this process and provide data that challenge and expand current thi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210342
Entities
People
- Edward Graves
Organizations
- Stanford University
- United States Army