Discussion
tumor, cancers, toxicity, cancer, aggressiveness, cerebral edema, tumors
TUMOR, RECURRENCE, INFILTRATION, CANCERS, CANCER, DISEASE, RECRUITMENT, ADVERSE EFFECTS, CEREBRAL EDEMA, TUMOR GROWTH, TUMORS
This study showed that treating patients with the first recurrence of GBM with avelumab alone or in combination with bevacizumab and sequentially with anti-PD-1 inhibition is well tolerated, safe, and does not result in unreported adverse effects. However, the combination of LITT followed by avelumab (part B) had potential toxicity due to cerebral edema formation. The patients received dexamethasone more often and at higher doses after the LITT procedure than in part A. Baseline dexamethasone administration in patients receiving ICIs can result in decreased survival by affecting the innate and adaptive immune systems (There were no radiographic responses except for 3 patients who received avelumab combined with bevacizumab. A median OS of 13 months and 14.5 months for women is encouraging, despite no improvement in PFS as suggested by other studies. Nevertheless, we must be cautious in interpreting our results as our study was prematurely closed, not allowing for the planned accrual of the expansion cohort. In addition, we may have selected patients with smaller tumors for the LITT part of the study. Several factors can negatively influence the PFS of recurrent GBM treated with ICIs: (i) pseudoprogression, as the increased size of the lesions on MRI does not reflect the underlying biological mechanisms of recruitment and infiltration of immune cells into the tumor, (ii) the low mutation burden, lack of antigen presentation, presence of suppressive cytokines, and aggressiveness of the disease does not lead to an objective response but delays tumor growth, and (iii) the heterogeneity of the tumor, including the immune components, produces an array of intermixed results that are not appreciated with current imaging modalities, but ultimately leads to improved survival. Therefore, survival may be more relevant than objective response and PFS when treating patients with GBMs with ICIs as seen in other cancers (Five of the 6 patients with survival >12 months received combination treatment with bevacizumab, and a PR was reached in 3. The combination of bevacizumab with ICIs decreased the levels of VEGFA and other mediators of angiogenesis such as ANGPT2 and VEGFR2. ANGPT2 participates in resistance to the targeting of VEGF-A, with high levels associated with decreased response and survival of patients on ICI treatment (Our patients with lower γδ T cell levels had significantly higher survival rates. While γδ T cells are known to be cytotoxic to cancer cells by producing IFNγ and destroying tumor cells, there is increasing evidence that IL17-producing γδ T cells can promote tumor growth (Furthermore, we found prolonged survival in patients with lower CD4