JITC Editor Picks
Nina Shah, Jack Aiello, David E Avigan, Jesus G Berdeja, Ivan M Borrello, Ajai Chari, Adam D Cohen, Karthik Ganapathi, Lissa Gray, Damian Green, Amrita Krishnan, Yi Lin, Elisabet Manasanch, Nikhil C Munshi, Ajay K Nooka, Aaron P Rapoport, Eric L Smith, Ravi Vij, Madhav Dhodapkar
Journal for ImmunoTherapy of Cancer 2020;8:e000734 (12 July 2020)
Immunotherapy is currently playing a pivotal role in the treatment of multiple myeloma, with several approved antibody therapies and multiple other modalities including bispecific T cell engagers, CAR T cells and cancer vaccines in advanced clinical evaluation. Previously, in 2016, SITC published a consensus statement on immunotherapy for the treatment of hematologic malignancies, including acute leukemia, lymphoma and multiple myeloma. Recognizing the rapid pace of advancement of the field, and a need for practical guidance on how to incorporate the ever-growing number of immunotherapeutic agents into the treatment of multiple myeloma, SITC convened an expert panel encompassing perspectives from hematology, medical oncology, hematopathology, nursing and patient advocacy to provide evidence- and consensus-based recommendations for the oncology community on topics including patient selection, toxicity management, and quality of life considerations.
Julie N Graff, Tomasz M Beer, Joshi J Alumkal, Rachel E Slottke, William L Redmond, George V Thomas, Reid F Thompson, Mary A Wood, Yoshinobu Koguchi, Yiyi Chen, Emile Latour, Raymond C Bergan, Charles G Drake, Amy E Moran
Journal for ImmunoTherapy of Cancer 2020;8:e000642 (2 July 2020)
Checkpoint inhibition with anti-PD-1 monotherapy has shown minimal efficacy in prostate cancer, yet some studies have shown that patients with second-generation androgen receptor antagonist enzalutamide-resistant tumors display increased PD-L1 expression on circulating antigen-presenting cells. Hypothesizing that the addition of PD-1 inhibition after progression on androgen depravation could initiate a meaningful anti-cancer response, Julie N Graff et al enrolled 28 men with metastatic castration-resistant prostate cancer (mCRPC) in a single-arm phase II study of pembrolizumab given intravenously every 3 weeks for four doses along with enzalutamide. The primary endpoint was prostate-specific antigen decline of >=50%, which was achieved in five patients (18%). Median overall survival for the responders was 41.7 months (95% CI 22.16 to not reached), compared to 21.9 months (95% CI 14.7 to 28.4 months) for all patients. Three responders had baseline biopsies available, and none had detectable PD-L1 expression, though one had microsatellite instability high disease. Among patients with radiographically measurable disease, small discrepancies were observed between RECIST scoring and biopsied lesion-specific measurements. Exploratory biomarker analyses revealed significantly higher frequencies of granzyme B+ effector memory CD8+ T cells in responders compared to non- responders and a trend toward increased perforin+ effector memory CD8+ T cells in the responders. The study is the first to demonstrate durable responses with PD-1 checkpoint inhibition in a subset of patients with mCRPC and provide rationale for future trials of combination approaches.
David Chardin, Marie Paquet, Renaud Schiappa, Jacques Darcourt, Caroline Bailleux, Michel Poudenx, Aurélie Sciazza, Marius Ilie, Jonathan Benzaquen, Nicolas Martin, Josiane Otto, Olivier Humbert
Journal for ImmunoTherapy of Cancer 2020;8:e000645 (23 July 2020)
No reliable predictive and prognostic markers exist for patients treated with PD-(L)1 inhibitors for non-small cell lung cancer (NSCLC). David Chardin and colleagues prospectively enrolled 79 patients with NSCLC in a prospective trial to investigate the prognostic and predictive values for outcomes after anti-PD-1 therapy of baseline metabolic parameters from 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). For the 75 evaluable patients, high baseline metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were significantly associated with a lower overall survival (OS) and these parameters could also reliably predict early treatment discontinuation (ETD). Additionally, ETD was a strong surrogate marker for OS. In univariate analysis, patients who had not received previous chemotherapy had significantly higher MTV, while patients who had not received previous surgery or radiotherapy had significantly higher MTV and TLG. This is the largest prospective study to demonstrate that high baseline MTV is an independent predictive and prognostic factor in advanced NSCLC. Because 18F-FDG PET/CT is a noninvasive and whole-body scan that is available in routine practice, MTV could be a useful and simple tool to identify patients who may benefit from immunotherapy. Future trials stratifying patients by baseline FDG are needed to validate the utility of MTV as a prognostic and predictive biomarker.
Fangming Liu, Weiren Liu, Shuang Zhou, Chunhui Yang, Mengxin Tian, Guangshuai Jia, Han Wang, Bijun Zhu, Mingxiang Feng, Yan Lu, Tiankui Qiao, Xinxin Wang, Wei Cao, Xiangdong Wang, Yinghong Shi, Duojiao Wu
Journal for ImmunoTherapy of Cancer 2020;8:e000501 (1 July 2020)
T cell metabolism is critical for anti-cancer activity, and an understanding of altered energy usage by immune cell subsets in the tumor microenvironment may help inform the design of future immunotherapeutic strategies. To investigate metabolic perturbations in hepatocellular carcinoma (HCC), Fangming Liu and colleagues took advantage of single-cell RNA sequencing on 8047 sorted T cells from both HCC-adjacent healthy tissue and tumor cores. Of the eight stable cell clusters that emerged, two were identified as corresponding to exhausted CD8+ T cells. The gene encoding fatty acid binding protein FABP5 was specifically upregulated in the cluster of partially exhausted CD8+ T cells. Mitochondrial membrane potential and lipid uptake were increased in the cells with high FABP5 expression, though cellular neutral lipid content remained unchanged. Notable discrepancies in expression levels of tumor necrosis factor receptor superfamily mRNAs were observed between CD8+ T cell clusters, with roughly 85% of FABP5-positive T cells also expressing TNFRSF9, which encodes CD137 (4-1BB). Compared to CD28-based chimeric antigen receptor (CAR) T cells, CD137-costimulated CAR T cells displayed significant upregulation of genes associated with mitochondrial fatty acid oxidation as well as profoundly increased expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma). Inhibition of PPAR-gamma impaired survival and proliferation of CD137-costimulated CAR T cells. The presence of T cells with upregulated FABP5 expression and increased lipid uptake was validated in tumor samples from patients with non-small cell lung cancer; furthermore, FABP5-positive tumor infiltrating T cells were linked with improved overall and recurrence-free survival in 118 patients with HCC. The study provides rationale for further investigation of FABP5 as a potential prognostic immunometabolic biomarker in larger, longitudinal studies.
Marta Trüb, Franziska Uhlenbrock, Christina Claus, Petra Herzig, Martin Thelen, Vaios Karanikas, Marina Bacac, Maria Amann, Rosemarie Albrecht, Claudia Ferrara-Koller, Daniela Thommen, Sacha Rothschield, Spasenija Savic Prince, Kirsten D Mertz, Gieri Cathomas, Robert Rosenberg, Viola Heinzelmann-Schwarz, Mark Wiese, Didier Lardinois, Pablo Umana, Christian Klein, Heinz Laubli, Abhishek S Kashyap, Alfred Zippelius
Journal for ImmunoTherapy of Cancer 2020;8:e000238 (2 July 2020)
Ligation of the costimulatory receptor 4-1BB (CD137) by antigen-presenting cells or agonistic antibodies has been reported to enhance proliferation, effector functions, memory formation and survival in CD8+ T cells both in vitro and in vivo. However, single-agent systemic 4-1BB-targeting therapies have displayed disappointing efficacy or unmanageable toxicities in trials to date. Marta Trüb and colleagues investigated the immunostimulatory properties of a fibroblast activation protein (FAP)-targeted 4-1BB agonist (FAP-4-1BBL). In co-culture experiments with peripheral blood mononuclear cells from healthy donors and FAP-expressing fibroblasts, combination treatment with CD3-agonist antibody and FAP-4- 1BBL led to enhanced upregulation of activation markers CD25 and 4-1BB as well as proliferation marker Ki67. Exhausted tumor infiltrating lymphocytes (TILs) with high expression levels of inhibitory receptors PD-1, TIGIT, TIM-3, CD160, BTLA and Lag-3 that were freshly obtained from primary tumors of patients with non-small cell lung cancer and epithelial ovarian cancer displayed enhanced activation and effector functions after combination treatment with FAP-4-1BBL and either agonistic anti-CD3 or anti-tumor-antigen/anti-CD3 T cell bispecific antibodies. Both CD8+ and CD4+ TILs produced interferon gamma, IL-2 and tumor necrosis factor alpha after treatment with FAP-4-1BBL, and CD8+ TILs upregulated perforin production. Costimulation with FAP-4-1BBL also led to pronounced IL-13 secretion, as measured by high levels of the cytokine in TIL culture supernatants. Treatment with IL-13 led to detectable STAT6 phosphorylation in tumor cell lines and patient-derived cancer cells. Tumor cell lines exposed to supernatants from FAP-4-1BBL TILs significantly upregulated expression of active caspase 3. The work suggests IL-13 plays an important role in FAP-4-1BBL-mediated tumor cell apoptosis and offers rationale for a combination strategy to enhance the efficacy of bispecific antibodies against solid tumors.
Christopher A Chuckran, Chang Liu, Tullia C Bruno, Creg J Workman, Dario AA Vignali
Journal for ImmunoTherapy of Cancer 2020;8:e000915 (15 July 2020)
In the efforts to identify new therapeutic targets for cancer immunotherapy, receptors that affect unique T cell subtypes and functions may offer substantial advantages for potential combinatorial strategies for checkpoint blockade. One promising potential target is Neutropilin-1 (NRP1), which acts as a receptor ‘hub’ for sorting signals from diverse ligands to both promote regulatory T cell (Treg) stability in the tumor microenvironment and inhibit anti-tumor CD8+ T cell responses. In a timely and comprehensive review, Christopher Chuckran and colleagues discuss the evidence that that NRP1, in addition to mediating important functions including self-tolerance and immune homeostasis, also plays a key role in regulating intratumoral Treg cells and CD8+ T cells in the context of cancer. In addition to the evidence that NRP1 is important for Treg trafficking to tumors and for maintaining intratumoral Treg cell function and phenotype, circulating NRP1+ Tregs are detected at high levels in patients with cancer—a unique observation among all known immune receptors. Although most studies to date have focused on NRP1’s role in angiogenesis, one anti-NRP1 monoclonal antibody, ASP1948 (human IgG4, Astellas Pharma Inc), is currently being clinically assessed in combination with nivolumab in a phase Ib trial (NCT03565445) for inhibitory effect on Treg cell function, and results are expected in 2022.