Lana Kandalaft

Immunotherapy for ovarian cancer: towards a tailored immunophenotype-based approach

Despite documented evidence that ovarian cancer cells express immune-checkpoint molecules, such as PD-1 and PD-L1, and of a positive correlation between the presence of tumour-infiltrating lymphocytes and favourable overall survival outcomes in patients with this tumour type, the results of trials testing immune-checkpoint inhibitors (ICIs) in these patients thus far have been disappointing. The lack of response to ICIs can be attributed to tumour heterogeneity as well as inherent or acquired resistance associated with the tumour microenvironment (TME). Understanding tumour immunobiology, discovering biomarkers for patient selection and establishing optimal treatment combinations remains the hope but also a key challenge for the future application of immunotherapy in ovarian cancer. In this Review, we summarize results from trials testing ICIs in patients with ovarian cancer. We propose the implementation of a systematic CD8

Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Abstract Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell–infiltrated tumors. Significance: Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4+ effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors. This article is highlighted in the In This Issue feature, p. 1

Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation

Treatment of high-grade serous ovarian cancer (HGSOC) remains challenging. Although HGSOC can potentially be responsive to immunotherapy owing to endogenous immunity at the molecular or T cell level, immunotherapy for this disease has fallen short of expectations to date. This Review proposes a working classification for HGSOC based on the presence or absence of intraepithelial T cells, and elaborates the putative mechanisms that give rise to such immunophenotypes. These differences might explain the failures of existing immunotherapies, and suggest that rational therapeutic approaches tailored to each immunophenotype might meet with improved success. In T cell-inflamed tumours, treatment could focus on mobilizing pre-existing immunity and strengthening the activation of T cells embedded in intraepithelial tumour myeloid niches. Conversely, in immune-excluded and immune-desert tumours, treatment could focus on restoring inflammation by reprogramming myeloid cells, stromal cells and vascular epithelial cells. Poly(ADP-ribose) polymerase (PARP) inhibitors, low-dose radiotherapy, epigenetic drugs and anti-angiogenesis therapy are among the tools available to restore T cell infiltration in HGSOC tumours and could be implemented in combination with vaccines and redirected T cells.

Bevacizumab, Atezolizumab, and Acetylsalicylic Acid in Recurrent, Platinum-Resistant Ovarian Cancer: The EORTC 1508-GCG Phase II Study

Abstract Purpose: Treatment options for patients with platinum-resistant ovarian cancer (PROC) are limited, and new therapeutic strategies are urgently needed. This phase II, randomized, multicentre trial evaluated the safety and activity of the anti–PD-L1 antibody atezolizumab (atezo) combined with the VEGF inhibitor bevacizumab (bev) and the irreversible cyclooxygenase 1/2 inhibitor aspirin [acetylsalicylic acid (ASA)] in PROC. Patients and Methods: Patients were randomized to bev monotherapy 15 mg/kg (arm 1), atezo 1,200 mg plus placebo (pbo; arm 2), atezo 1,200 mg plus ASA 320 mg/daily (arm 3), bev 15 mg/kg plus atezo 1,200 mg plus pbo (arm 4), or bev 15 mg/kg plus atezo 1,200 mg plus ASA 320 mg/daily (arm 5). Primary endpoint was progression-free survival at 6 months (PFS-6) according to RECIST v1.1 assessed by a local investigator. Secondary objectives included overall survival, PFS, second PFS (PFS2), and tolerability. Time to first subsequent therapy (TFST) was evaluated in a post hoc analysis. Results: In arms 1 (bev), 4 (bev–atezo–pbo), and 5 (bev–atezo–ASA), there were 7/32 [21.9%, 70% confidence interval (CI), 14.0–32.0], 8/32 (25.0%, 70% CI, 16.6–35.3), and 8/32 (25.0%, 70% CI, 16.6–35.3) patients alive and progression-free at 6 months. The primary objective was not reached in any arm. Median PFS and response rates were 2.3 for bev monotherapy, 4.1 for bev–atezo–pbo, and 4.0 months for bev–atezo–ASA and 10%, 19%, and 15%, respectively. Two patients achieved an ongoing complete response lasting for more than 5 years from randomization (1 in bev–atezo–pbo and 1 in bev–atezo–ASA). A post hoc analysis of TFST suggested benefit of adding bev to atezo–ASA (P < 0.001). Tumor-infiltrating lymphocytes (TIL) increased in the atezo-containing arms after the first two cycles, and increased TIL were associated with a significantly longer TFST. Conclusions: The addition of ASA to bev plus atezo was well-tolerated but did not improve efficacy in PROC. Relative to bev alone, the bev plus atezo combination numerically improved PFS. Exploratory translational analyses suggest clinical benefit in a subgroup of patients characterized by high TIL infiltration and PD-L1–positive tumors at baseline.

A phase 1 trial of adoptive transfer of vaccine-primed autologous circulating T cells in ovarian cancer

We have previously shown that vaccination with tumor-pulsed dendritic cells amplifies neoantigen recognition in ovarian cancer. Here, in a phase 1 clinical study ( NCT01312376 /UPCC26810) including 19 patients, we show that such responses are further reinvigorated by subsequent adoptive transfer of vaccine-primed, ex vivo-expanded autologous peripheral blood T cells. The treatment is safe, and epitope spreading with novel neopeptide reactivities was observed after cell infusion in patients who experienced clinical benefit, suggesting reinvigoration of tumor-sculpting immunity.