Abstract
INTRODUCTION
Recent Phase III clinical trial findings indicate a failure of anti-PD-1 mAb (nivolumab) monotherapy to increase overall survival (OS) for recurrent glioblastoma (GBM) patients. Supportingly, we previously demonstrated that, while neither mono- nor dual-therapy with anti-PD-1, radiotherapy, or an IDO1 inhibitor, leads to long-term survival, the trimodal combination of all three durably increases survival in ~40% of mice with well-established, intracranial, syngeneic GL261. A concern arose, however, as to why ~60% of subjects always succumb to brain tumor, regardless of treatment. Psychological stress is a well-known modifier of the immune response, although the impact of psychosocial stressors on immunotherapeutic effectiveness have yet to be investigated in GBM. Because single-mouse housing induces chronic stress, we wondered if psychological factors diminish immunotherapeutic efficacy.
METHODS
C57BL/6 mice were housed singly (n=10) or at five mice/cage (normally; n=10) for one week, prior to the intracranial injection (ic.) of 2 × 105 GL261 cells. At fourteen days post-ic., subjects were treated with trimodal immunotherapy as previously reported (Ladomersky et al., 2018; CCR).
RESULTS
Trimodal treatment leads to a median OS of 17.5 days in singly-housed subjects, which is significantly decreased as compared to the 29 day OS for normally-housed subjects (P=0.037). Strikingly, long-term survivors were only observed in the normally-housed group. Subjects were treated with RT and PD-1/IDO1 inhibitors, with and without the anxiety inhibiting pharmacologic, propranolol. While there was no difference in OS between subjects treated with IgG control or propranolol, alone, 60% of mice treated with all four agents survived long-term, whereas only 30% survived long-term with trimodal immunotherapy, alone (P=0.001).
CONCLUSIONS
Given the association between higher anxiety levels, and an increased mortality rate among cancer patients in the U.S., these data suggest that, inhibiting stress-signaling pathways may synergize to improve immunotherapeutic efficacy, specifically improved likelihood of sustained response, for patients with malignant glioma.