JITC Editor Picks
Heather L. MacGregor, Azin Sayad, Andrew Elia, Ben X. Wang, Sarah Rachel Katz, Patricia A. Shaw, Blaise A. Clarke, Sarah Q. Crome, Celine Robert-Tissot, Marcus Q. Bernardini, Linh T. Nguyen & Pamela S. Ohashi
Journal for ImmunoTherapy of Cancer 2019, 7:357 (31 December 2020)
Checkpoint inhibitors targeting the PD-1/PD-L1 axis have yielded disappointingly low overall response rates in epithelial ovarian cancer (EOC), which remains the foremost cause of death among gynecological malignancies. Clinical trials investigating agents targeting other members of the B7 protein family beyond PD-L1 are ongoing, yet the expression patterns of these key immune-regulatory cell-surface protein ligands remains poorly defined in the context of EOC. Using flow cytometry, immunohistochemistry, and genomic analyses, Heather MacGregor et al. determined the patterns of B7-H3, B7-H4 and PD-L1 expression by tumor, stromal, and immune cells in the ovarian tumor microenvironment. Stromal cells of the ovarian TME expressed high levels of B7-H3 whereas B7-H4 expression was restricted to tumor cells. The proportion of tumor cells calculated from H&E stained slides strongly correlated with the proportion of B7-H3low cells as assessed by flow cytometry, indicating that B7-H3 can be used to assess the tumor-to-stroma ratio. High tumor-to-stroma ratio was associated with higher frequencies of PD-1high CD8+ T cells, and increased PD-L1 expression by antigen-presenting cells. Expression of PD-L1 was also restricted to stromal cells, which suggests that combination therapies against both molecules will target different cell populations in the ovarian TME offering opportunities for additive or synergistic effects.
Guillaume Manson, Alexandre Thibault Jacques Maria, Florence Poizeau, François-Xavier Danlos, Marie Kostine, Solenn Brosseau, Sandrine Aspeslagh, Pauline Du Rusquec, Maxime Roger, Maud Pallix-Guyot, Marc Ruivard, Léa Dousset, Laurianne Grignou, Dimitri Psimaras, Johan Pluvy, Gilles Quéré, Franck Grados, Fanny Duval, Frederic Bourdain, Gwenola Maigne, Julie Perrin, Benoit Godbert, Beatris Irina Taifas, Alexandra Forestier, Anne-Laure Voisin, Patricia Martin-Romano, Capucine Baldini, Aurélien Marabelle, Christophe Massard, Jérôme Honnorat, Olivier Lambotte & Jean-Marie Michot
Journal for ImmunoTherapy of Cancer 2019, 7:337 (3 December 2020)
Paraneoplastic syndromes (PNSs) are rare but potentially serious autoimmune disorders that specifically arise in cancer patients. Little is known about the use of immune checkpoint inhibitors in patients with PNSs, and Guillame Manson and colleagues have undertaken the first study to describe the tolerability of immunotherapy in this population. In a nationwide, observational, multicenter study, 1304 adult patients who had received anti-PD-1 or anti-PD-L1 therapy in France were screened and PNSs were identified in 32 (2.45%). Of the 32 PNS cases, 16 were pre-existing prior to the initiation of checkpoint blockade and 16 arose after patients received therapy. Half of the patients with pre-existing PNSs experienced worsening of symptoms with anti-PD1 or anti-PD-L1 therapy. In the cohort of patients who presented with PNSs after the initiation of immunotherapy, neurologic conditions were the most frequently observed pathologies (n=7). Four patients died as a result of progression of a neurologic PNS—a rare but serious adverse event revealed by the large-scale survey that might not have been apparent in individual studies or clinical trials. The results show that PNSs may be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy underscoring the importance for physicians to carefully monitor patients for autoimmune pathology when inititating immunotherapy.
Brian I. Rini, Dena Battle, Robert A. Figlin, Daniel J. George, Hans Hammers, Tom Hutson, Eric Jonasch, Richard W. Joseph, David F. McDermott, Robert J. Motzer, Sumanta K. Pal, Allan J. Pantuck, David I. Quinn, Virginia Seery, Martin H. Voss, Christopher G. Wood, Laura S. Wood & Michael B. Atkins
Journal for ImmunoTherapy of Cancer 2019, 7:354 (20 December 2020)
Position Article and Guidelines
For more than 20 years, cytokine therapy, such as high-dose IL-2, was the only option for immunotherapy-based treatment of advanced renal cell carcinoma (aRCC). Since 2015, a series of approvals has vastly expanded the available options in the immunotherapy repertoire, motivating the Society for Immunotherapy of Cancer to reconvene the Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee, chaired by Brian Rini and Michael Atkins, to generate updated consensus recommendations for the treatment of patients with aRCC. Drawing upon evidence from multiple phase 3 trials, the new consensus statement advocates that all aRCC patients should receive regimens containing checkpoint inhibitors as front-line therapy. Potential biomarkers for identifying the patients who will derive the most benefit and the role of immunotherapy in non-clear cell pathology are also discussed. Additionally, the consensus statement describes strategies for monitoring response to treatment, managing toxicities and supporting quality of life in patients receiving immunotherapies, all of which may differ markedly from traditional approaches due to the unique nature of immunotherapy agents. The guidelines will be a valuable resource for the oncology community.
Julie Voeller, Amy K. Erbe, Jacob Slowinski, Kayla Rasmussen, Peter M. Carlson, Anna Hoefges, Sabrina VandenHeuvel, Ashley Stuckwisch, Xing Wang, Stephen D. Gillies, Ravi B. Patel, Alvin Farrel, Jo Lynne Rokita, John Maris, Jacquelyn A. Hank, Zachary S. Morris, Alexander L. Rakhmilevich & Paul M. Sondel
Journal for ImmunoTherapy of Cancer 2019, 7:344 (6 December 2020)
Immunotherapy for the treatment of solid cancers in children has generally had limited success, in part because these tumors are characterized by low mutation burdens with few neoantigens and limited immune cell infiltration. Using mouse models of neuroblastoma (the most common extracranial solid cancer in pediatrics), Julie Voeller and colleagues developed a novel innate and adaptive immunotherapeutic approach that generated potent antitumor effects as well as memory responses against an immunologically “cold” tumor. To simulate clinically high-risk disease, Voeller et al. generated an N-MYC driven, low TMB, and high-GD2-expressing syngeneic murine neuroblastoma model. Tumor regression was achieved in 80% of mice following treatment with external beam radiation therapy and intratumoral injection of a novel immunocytokine fusion protein consisting of human anti-GD2 mAb linked to IL-2 in combination with anti-CTLA-4 and CpG and anti-CD40. Upon rechallenge, there was significant slowing of tumor growth, with average tumor volumes on day 30 of 15.4 mm3 in previously treated mice compared to 51.5 mm3 in naïve mice (p = 0.012). The combination treatment also led to increased numbers of tumor-infiltrating CD4+ T cells, higher numbers of monocytes/macrophages, an elevated CD8+ to Treg ratio and a reduction of Tregs compared to controls. Such novel immunotherapeutic approaches could potentially improve outcomes while reducing reliance on genotoxic high-dose chemotherapy and radiation.
Erik Voets, Marc Paradé, David Lutje Hulsik, Sanne Spijkers, Wout Janssen, Joost Rens, Inge Reinieren-Beeren, Gilbert van den Tillaart, Sander van Duijnhoven, Lilian Driessen, Maurice Habraken, Peter van Zandvoort, Joost Kreijtz, Paul Vink, Andrea van Elsas & Hans van Eenennaam
Journal for ImmunoTherapy of Cancer 2019, 7:340 (4 December 2020)
Numerous human cancers overexpress CD47, a “don’t eat me” checkpoint molecule found on red blood cells and platelets among other tissues that primarily acts on myeloid lineage cells through interaction with the inhibitory immune receptor signal-regulatory protein alpha (SIRPalpha). Agents targeting CD47 have demonstrated encouraging anti-tumor responses in clinical trials. However two studies were halted due to toxicity such as severe anemia and thrombocytopenias. To avert potential on-target toxicity and overcome the antigen sink effects of the broad expression pattern of CD47, Erik Voets and colleagues generated a humanized anti-SIRPalpha antibody, with potent binding across the most abundant alleles among the human population. The antibody, ADU-1805, enhanced rituximab-mediated phagocytosis of Raji cells by human macrophages and trogocytosis by neutrophils. Unlike anti-CD47 antibodies, ADU-1805 did not affect T cell activation and proliferation, nor did it bind red blood cells or platelets or trigger hemagglutination in vitro. Safety and pharmacodynamics of ADU-1805 were established in vivo in a single dose infusion in cynomologus monkeys, where administration was well-tolerated and none of the primates developed anemia. The results support further development of ADU-1805 as a novel checkpoint inhibitor with favorable safety profile compared to other agents targeting the CD47/SIRPalpha axis.