Categories | Guiding factors | Points |
Basics of radiotherapy | Clinical application of radiotherapy | Curative or palliative treatments can lead to responses such as immunomodulation within TME and immune suppression in both TME and normal tissue (lymphopenia). (Note: the immune modifier may or may not be synergistic with radiotherapy in the more classic ‘radiation sensitizer’ approach). Influenced and controlled by the extent of normal tissue tolerance, genetic composition of the host, microbiome, immune profiling (immunotype of the patient) and complex cell-cell relationship within the microenvironment. |
Delivery of radiation therapy* | Differentiate immune mechanisms between SOC or non-SOC delivery approaches including dose-heterogeneity, field size (dose point calculation), with non-conventional fractionation and dose size and dose rate (such as low-dose, ablative/subablative, hyperfractionation/hypofractionation, high-LET, proton†, flash, grid, lattice, TRT and chemoradiation). | |
Mechanisms | Radiation-immuno-dose | Inducible mechanisms include non-immune mechanisms (such as DNA-repair (may be immune modulating) and other signal transduction) and targetable adaptation. Inducible immune events include stimulation of antigen/neoantigen expression/presentation, pro-inflammatory immune modulation within the tumor, converting immunosuppressed tumor to highly immunogenic tumor that will synergize with checkpoint inhibitors, CAR-T cells and other immunotherapeutic agents. |
Immune modulators | Immunotherapy compatibility | Matching the mechanism of action of immunotherapeutic agents with radio-immuno dose-fractions. |
Tools for clinical trials | Common critical elements of clinical trial design between radiation therapy and immunotherapy Common repository of deidentifed clinical trial data to study different schedules Include both government and industry trial studies | Patient safety, patient benefits and establish the right response criteria and end points to prove the efficacy of such opportune combinations with radiation and immunotherapy. Clinical trial designs should be based on robust preclinical data originating from in vitro, in vivo and veterinary models and also from bedside-to-bench (reverse translational). Randomization and coordination among investigators (radiation oncologists and medical oncologists) is vital to compare various regimens. Incorporation of robust biomarkers, including imaging and tumor tissue/blood-based immune profiling. Expert mathematical analysis of complex clinical outcome data with many interacting factors is required. |
*Treatment options determined in part by acceptable/allowable standards of care and reimbursement.
†The complexity of adding two investigative approaches—novel radiation plus immune modulation require stepwise understanding.
CAR-T, chimeric antigen receptor-T; LET, linear energy transfer; SOC, standard-of-care; TME, tumor microenvironment.