Impact of sublethal radiation dose on tumor response, microenvironment and the immune system
Joachim Yahalom
MDMemorial Sloan Kettering Cancer Center
Project Term: July 1, 2022 - June 30, 2025
Extremely low dose radiation can improve blood cancer outcomes. But the mechanisms of how sublethal radiation (SRT) affects tumors, the microenvironment and immune system remain unclear. We envision a broad, nuanced role for SRT with benefits across diverse clinical situations and propose 3 clinical trials with deep translational components. Each can be paradigm-changing, but are thematically unified to improve mechanistic understanding of how such exceptionally small doses might offer so much.
Radiotherapy (RT) is a highly effective treatment for many lymphomas, playing an important role both by itself and in combination with systemic therapies for both palliation and cure. It has been observed for decades that blood cancer cells can be exquisitely sensitive to RT. Importantly, cells seem to remain radiosensitive even if a patient has widespread disease or has received numerous prior lines of therapy. This radiosensitivity is important since it has enabled us to use more moderate doses of RT as compared to the doses typically utilized for other non-blood cancers (i.e., breast or prostate cancer). Nearly 20 years ago, it was first observed serendipitously that extremely low doses of radiation could produce long-lasting remissions and even cures for certain indolent lymphomas. Since then, our group has repeatedly demonstrated the often-amazing responses which can be derived from doses which are classically “too low” to treat cancers. Given these impressive outcomes, the very low dose RT (VLDRT) concept has become a key research program for our group.
The benefits of VLDRT are numerous and were only solidified during the recent COVID-19 pandemic. Reducing the number of RT treatments required down from 25-30 to just 1-2 sessions offers clear benefits in terms of logistical convenience, financial burden and minimizes the time off systemic therapies. Most importantly for patients, VLDRT is associated with extremely minimal side effects. Despite clear advantages, there remain numerous unanswered clinical and biologic questions including why this regimen works so well. In fact, utilization of VLDRT outside of a very narrow indication (palliation of patients with indolent lymphomas like follicular or marginal zone lymphoma) remains highly controversial in the field of radiation oncology. However, we hypothesize that this indication is just the tip of the iceberg in terms of potential benefit for patients.
This grant would support several initiatives all designed to study the benefit of sublethal doses of RT and to better understand the mechanisms of its efficacy. We hypothesize that VLDRT can play important roles not just for palliation, but also a) as a curative treatment for select patients, b) as a tool to strengthen immune responses and tumor-fighting efficacy in patients receiving advanced cellular or immunotherapies like chimeric antigen receptor T-cells or c) as a strategy to provide temporary symptomatic relief to enable patients to get maximal benefit from certain slower-acting systemic therapies. This grant will support several prospective clinical trial initiatives which we believe have the potential to be paradigm changing for lymphoma patients. We intend to assess the utility of VLDRT across several types of lymphomas both indolent and aggressive. Furthermore, we have assembled a truly multidisciplinary team of experts to study the biology of this approach and offer insights into other situations where it might offer benefit.