Discussion
There is a paucity of therapeutic options and no validated standard of care for rHGG. This retrospective series demonstrated ICI with concurrent re-irradiation using SBRT can be safely delivered in rHGG. Preclinical data provides a rationale for evaluating ICI in this clinical setting (21, 24). The statistically significant increase in post-treatment tumor volumes identified within our cohort may in part have reflected a component of pseudoprogression related to ICI. Prior studies associate ICI treatment response with a preceding increase in tumor volume related to intratumoral immune cell infiltration, resulting in a transient inflammatory reaction (25).
Understanding ICI response requires further elucidation of the intratumoral milieu and systemic immune response (26-31). Several studies support preoperative ICI enhance expression of chemokine transcripts including interferon-γ, increase immune cell infiltration, and augment T cell receptor clonal diversity, but with conflicting clinical results (32, 33). One putative explanation for suboptimal immune response is the high rate of lymphopenia observed in HGG patients, with one group reporting that T cells are available in this population but are sequestered in the bone marrow (34).
The aforementioned studies provide a rationale for optimizing immunotherapeutic efficacy through its implementation in an immunologically favorable setting, such as priming the immune system to tumor-specific antigens. RT may improve ICI effects by increasing the quantity and diversity of intracellular peptides, increasing MHC class I expression, and promoting T cell recruitment and infiltration (20-22, 35-38). Technological advancements in the delivery of SBRT allow for highly conformal treatments that significantly reduce the toxicity associated with re-irradiation in other disease sites (16). Several studies show an improvement in functional status and discontinuation of corticosteroid usage following SBRT monotherapy with a low risk of late central nervous system toxicity (14, 15, 17, 18, 39). Additionally, SBRT dose-fractionation schemes may be more effective than conventionally fractionated RT with regard to augmenting immune responses (22, 40). This option also allows RT completion within one to five treatments, which is convenient for patients.
A closer look at this cohort notes several limitations that could be considered in future studies geared towards optimizing a response. Most patients had multiple recurrences and subsequently received various systemic treatments either on or off clinical trials. There was a mean of 4.5 lines of treatment administered with ICI+SBRT therapy given as the last line in 8 of these patients. There is a possibility that these prior treatments negatively impacted the ability to prime the immune system, and a more robust response may be seen if treated with ICI + SBRT at first recurrence. Patients were treated without knowing PD-L1 expression status. A few reports show higher response rates with increased expression in other malignancies (41), however the prognostic value of PD-L1 for HGG is still under investigation. While foundational analyses were available, advanced correlation studies were limited by the cohort size. Two-thirds of the patients in this cohort were on dexamethasone while receiving ICI which may interfere with the ICI efficacy.
The optimal treatment approach for patients with rHGG continues to be an area of ongoing investigation. This small retrospective study suggests ICI can be safely given concurrently with re-irradiation using SBRT for patients with rHGG. These initial findings support evaluating whether optimizing conditions for combinatory ICI + SBRT approaches may lead to favorable clinical responses, or whether attention should be turned to other therapeutic avenues to address this unmet need in neuro-oncology.