November 2023
The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Social Media Editor Dr. Praveen Bommareddy.
Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial by Routy et al
Nature Medicine (2023)
Combination therapy with immune checkpoint inhibitors has revolutionized treatment for melanoma, but there is still a significant proportion of patients who either fail to respond or progress after a brief period of response, thus there is still a need for new therapies/modalities that can complement immune checkpoint inhibitors. In a phase I trial published in Nature Medicine, Routy et al have shown, for the first time, that healthy donor fecal microbiota transplantation (FMT) plus anti-PD1 immunotherapy was safe and potentially enhanced the activity of immunotherapy in advanced melanoma patients in the first-line setting. FMT was only linked to grade 1 or 2 side effects, and there were no new or unexpected immune-related adverse events from the combination therapy. The objective response rate was 65% (13 of 20), including four (20%) complete responses. Authors have shown that donor microbiome engraftment analyzed by metagenomics and 16s rRNA gene sequencing was vital in determining the response to immunotherapy in melanoma patients post-FMT. They also showed that increased histidine levels in plasma samples of patients post-FMT were predictive of response. Higher levels of activated CD8+ T-cells and Mucosal-associated invariant T (MAIT) cells were seen in responder patients. Furthermore, the donor stool induced a response in animals, while patient stool samples at baseline failed to mount a response to anti-PD1 therapy in pre-clinical mouse models. These findings show that healthy donor FMT is safe in melanoma patients, which can improve the scalability of FMT in oncology settings, as previous FMT studies only used patient donors.
Clinical trial links oncolytic immunoactivation to survival in glioblastoma by Ling et al
Nature (2023)
Treatment options for glioblastoma (GBM) are limited and most patients recur within 6 months after surgical resection. There is an urgent need to develop new therapies for GBM. A first-in-human phase I clinical trial of CAN-3110, a replication-competent oncolytic herpes simplex virus 1 (oHSV) in 41 recurrent high-grade glioma (rHGG) patients, was recently published in Nature by Ling et al. CAN-3110 retains expression of a viral gene (g1 34.5 encoding the viral protein ICP34.5) responsible for wild-type HSV1 neuroinflammation, under the control of a tumor-specific promoter. The trial demonstrated the safety of this therapeutic approach with a median survival time (MST), 11.6 months (95% CI = 7.8–14.9 months). Further, a significant survival advantage was observed in GBM patients who were HSV1 seropositive prior to therapy as well as HSV1 seronegative patients who seroconverted after treatment. This finding seems to be unique to GMB as previous data with oncolytic HSV-1 showed no difference in response rates between serological subtypes in melanoma. There was also prolonged viral persistence and probable replication in many patients even months to years after injection. However, viral persistence was not associated with better outcomes being largely restricted to the shorter surviving HSV1 seronegative patients. Profiling of paired tumors before and after CAN-3110 revealed: 1) Significantly increased numbers of CD4+ and CD8+ T cells following therapy. These increased T cell numbers were correlated with prolonged survival in HSV1 seropositive, but not in seronegative patients; 2) Prolonged survival in seropositive patients was also associated with higher TCRβ diversity and; 3) Transcriptomic signatures of immune activation following therapy, including increased tumor myeloid cell signatures associated with “M1” immune-activating” functions. In sum, these results show that CAN-3110 generates immune activation in recurrent GBM and that this activation is associated with prolonged survival for patients with positive serology against HSV1. A new multi-center study has now started, funded by Break Through Cancer.
Perioperative Durvalumab for Resectable Non–Small-Cell Lung Cancer by Heymach et al
N Engl J Med (2023)
Lung cancer is the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) accounting for over 80% of cases. Surgery remains the primary curative-intent treatment for eligible patients with early-stage NSCLC. Approximately 40-50% of patients recur within 5 years after surgery, which can increase the risk of death. In this paper the authors report the primary analyses of event-free survival and pathological complete response from the phase III trial, which investigated the use of durvalumab administered perioperatively (i.e., as neoadjuvant and adjuvant therapy) along with neoadjuvant chemotherapy in patients with resectable NSCLC. 802 were randomly assigned to receive durvalumab (400) or placebo (402). Perioperative durvalumab plus neoadjuvant chemotherapy, as compared with neoadjuvant chemotherapy alone, was associated with significantly better results with regard to the two primary end points of event-free survival (hazard ratio for disease progression, recurrence, or death, 0.68; P = 0.004) and pathological complete response (difference in proportions, 13.0 percentage points; P<0.001), with a safety profile that was consistent with the individual agents. Based on these results, perioperative durvalumab plus neoadjuvant chemotherapy should be considered as a potential new treatment option for patients with resectable NSCLC.
Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results by Diab et al
J Clin Oncol (2023)
This study with negative results highlights the complexity of drug development and emphasizes the need to conduct thorough phase I/II studies with evidence of single agent anti-tumor activity before proceeding with larger phase III studies. Cytokine therapy, particularly with interleukin-2 (IL-2), has been approved for the treatment of advanced melanoma. High-dose IL-2 monotherapy has shown efficacy, including durable complete responses (CRs), in patients with metastatic melanoma and is approved for this population. However, its use is limited because of significant toxicities and the complex inpatient drug administration. Bempegaldesleukin (BEMPEG) is a pegylated IL-2 cytokine prodrug engineered to activate the clinically validated IL-2, with the goal of specially activating CD8+ T cells designed to harness the benefits of IL-2 while overcoming the historical challenges with toxicity. 783 patients were randomly assigned to receive either BEMPEG plus nivolumab (391 patients) or nivolumab monotherapy (392 patients). The overall response rate (ORR) per blinded independent central review was 27.7% (95% CI, 22.4 to 33.4) with combination therapy and 36.0% with nivolumab, the disease control rate was 56.1% and 58.5%, respectively. The study did not meet its three primary endpoints of ORR, progression- free survival, or overall survival with BEMPEG plus nivolumab combination therapy, providing no added clinical benefit compared with nivolumab monotherapy in patients with previously untreated, unresectable, or metastatic melanoma. There were no new safety signals identified. It will be important to further assess the pharmacodynamic, mechanism of action, and biomarker results from this study to determine if the lack of enhanced efficacy with the combination is due to the challenges targeting the IL-2 pathway or due to the specific drug design of BEMPEG. The translational data generated from PIVOT IO 001 may inform the development of other IL-2 and other cytokine pathway agonists that are able to demonstrate efficacy in combination with check point inhibitors.