Immunotherapy and Radiotherapy as an Antitumoral Long-Range Weapon—A Partnership with Unsolved Challenges: Dose, Fractionation, Volumes, Therapeutic Sequence

Abstract

Immunotherapy, the modern oncological treatment with immune checkpoint inhibitors (ICIs), has been part of the clinical practice for malignant melanoma for more than a decade. Anti-cytotoxic T-lymphocyte antigen 4 (CTLA4), anti-programmed cell death Protein 1 (PD-1), or anti programmed death-ligand 1 (PD-L1) agents are currently part of the therapeutic arsenal of metastatic or relapsed disease in numerous cancers; more recently, they have also been evaluated and validated as consolidation therapy in the advanced local stage. The combination with radiotherapy, a treatment historically considered loco-regional, changes the paradigm, offering—via synergistic effects—the potential to increase immune-mediated tumor destruction. However, the fragile balance between the tumoricidal effects through immune mechanisms and the immunosuppression induced by radiotherapy means that, in the absence of ICI, the immune-mediated potentiation effect of radiotherapy at a distance from the site of administration is rare. Through analysis of the preclinical and clinical data, especially the evidence from the PACIFIC clinical trial, we can consider that hypofractionated irradiation and reduction of the irradiated volume, in order to protect the immune-infiltrated tumor microenvironment, performed concurrently with the immunotherapy or a maximum of 2 weeks before the start of ICI treatment, could bring maximum benefits. In addition, avoiding radiation-induced lymphopenia (RILD) by protecting some anatomical lymphoid structures or large blood vessels, as well as the use of irradiation of partial tumor volumes, even in plurimetastatic disease, for the conversion of a "cold" immunological tumor into a “hot” immunological tumor are modern concepts of radiotherapy in the era of immunotherapy. Low-dose radiotherapy could also be proposed in plurimetastatic cases, the effect being different (modeling of the TME) from that of high doses per fraction irradiation (cell death with release of antigens that facilitates immune-mediated cell death).

The need for paradigm shift: prognostic significance and implications of standard therapy-related systemic immunosuppression in glioblastoma for immunotherapy and oncolytic virotherapy

“…Eligibility criteria, particularly relevant in neuro-oncology, and inadequate phase II study designs have been critically reviewed elsewhere ( 239 ). As for the design of clinical trials for glioblastoma to improve the effectiveness of immunotherapy/oncolytic virotherapy in general, the following aspects, supported by clinical data, must be taken into account ( 196 , 197 , 240 , 241 ). First, the circulating blood within the blood vessels is recognized as an organ at risk for radiotherapy.…”

“…An increasing number of studies have reported an association between the radiotherapy dose/volume and lymphopenia in glioblastoma ( 56 , 77 , 192 , 193 ). The severity of radiation-induced lymphopenia depends on the technique of radiotherapy, fraction number (fractionation regimen), dose per fraction (irradiation dosage), field size, and other variables ( 78 , 194 – 197 ).…”

Global research landscape and trends of cancer radiotherapy plus immunotherapy: A bibliometric analysis

“…The radiation dose, fractionation schedule, and radiation volume should be carefully formulated according to the individual context of each patient to avoid severe lymphopenia. To mitigate radiation-induced lymphopenia, hypofractionated radiation, reduction of the traditional clinical target volume, sparing healthy regional lymph nodes, where the T cell priming and activation takes place, and large blood vessels are worth exploring in the modern era of immunotherapy and technological improvements in targeting and delivery of RT [ 91 , 92 ].…”

Immunotherapy with PD-1 Inhibitor Nivolumab in Recurrent/Metastatic Platinum Refractory Head and Neck Cancers—Early Experiences from Romania and Literature Review

“…Immunosuppression induced via concurrent radiochemotherapy–immunotherapy, as well as the immunosuppression associated with elective irradiation of lymph nodes, could be the cause of failures reported in clinical trials such as JAVELIN Head and Neck 100 (NCT02952586). Even if it refers to Pembrolizumab, an ICI agent other than Nivolumab, a sequential combination is considered optimal in the case of delivering radio-chemotherapy and immunotherapy [ 52 , 53 , 54 , 55 ].…”