Abstract
Drug development in oncology today routinely focuses on approaches that utilize the patients’ immune system to destroy the malignancy. Combinatorial approaches of antineoplastic agents, both new and old, are being incorporated in the armamentarium of cancer treatments. The overarching goal of therapy remains the achievement of a complete and durable response with long term remission or cure. One approach in advancing treatment is aimed at strategies that improve immunological memory to induce long lasting immunity against the tumor. Although radiation therapy has not traditionally been thought to elicit an immunological effect, an increasing number of reports document the induction of an immune response against a tumor that kills cancer cells distant to the original site of treatment after local irradiation to a tumor. This phenomenon is called an abscopal effect. Since radiation alone is rarely associated with such a response, it is being combined with immuno-oncology drugs in an attempt to enhance response. One such strategy combines sargramostim, a recombinant human granulocyte macrophage colony stimulating factor (rhu GM-CSF), with radiotherapy. GM-CSF is a cytokine secreted by multiple cells types that promotes maturation of dendritic cells and enables the presentation of tumor-associated antigens to generate a T-cell response. This review article discusses the outcomes of clinical trials and case reports examining the efficacy and safety of combining radiation therapy with this immunomodulatory agent. We will also examine future studies and challenges facing the translation of this therapeutic approach.
Highlights
BackgroundThe synergy between immunotherapy and radiotherapy is being used to enhance therapeutic responses
The biological functions of GM-CSF are mediated through binding of its receptor (GM-CSFR) which triggers downstream signaling pathways such as Janus kinase-signal transducer and activator of transcription (JAK-STAT), phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signaling [1,2,3]
These studies and reports suggest the combination of radiation therapy with sargramostim may result in an abscopal response in patients with solid tumors, but further research is necessary to validate these findings
Summary
The synergy between immunotherapy and radiotherapy is being used to enhance therapeutic responses. A case report described an abscopal response in a patient diagnosed with stage IIIB, unclassifiable non-small cell lung cancer (NSCLC) treated with local radiotherapy in combination with oncothermia and sargramostim [18]. Multiple metastatic lymph nodes distal from the site of radiation demonstrated nearly a complete remission Some data suggest this approach could enhance the immune response by locally increasing tumor oxygenation, perfusion, natural killer cell activity and trafficking of dendritic cells to the lymph nodes. To get a better understanding of future studies investigating the combination of radiotherapy in conjunction with sargramostim, the ClinicalTrials.gov database was queried using the search terms: GM-CSF, GMCSF, Granulocyte-Macrophage Colony-Stimulating Factor, sargramostim and Leukine This search identified 445 trials, which were individually assessed to determine if the listed trial included radiation as treatment modality in each study (database accessed December 8, 2018).
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