JITC Editor Picks
John C Flickinger Jr, Jagmohan Singh, Robert Carlson, Elinor Leong, Trevor R Baybutt, Joshua Barton, Ellen Caparosa, Amanda Pattison, Jeffrey A Rappaport, Jamin Roh, Tingting Zhan, Babar Bashir, Scott A Waldman, Adam E SnookJournal for ImmunoTherapy of Cancer 2020;8:e001046 (20 August 2020)
The adenovirus serotype 5 (Ad5) vector is commonly used as a backbone for cancer vaccines, however, pre-existing antibodies to Ad5 are present in more than 70% of the world’s population due to previous exposure via natural infection. To expand the population who may benefit from Ad5-based vaccine strategies, John C Flickinger Jr et al generated a chimeric vector with the fiber of Ad5 replaced by that of Ad35 (Ad5.F35) and carrying the gastrointestinal cancer antigen guanylyl cyclase C (GUCY2C). No toxicity signals were observed with the Ad5.F35-based vaccine in mouse models, and long-lasting T cell responses were observed against the GUCY2C antigen after vaccination. In challenge models, both Ad5- and Ad5.F35-based vaccines produced GUCY2C-specific CD8+ T cells of comparable avidity and both had identical efficacy in reducing tumor burden, slowing disease progression, and promoting survival. The numbers of antigen-specific CD8+ T cells elicited by vaccination were reduced to a lesser degree with pre-exposure to Ad5 in animals receiving the Ad5.F35-based vaccine compared to vaccination with the parental vector. In sera from patients with colorectal cancer enrolled in the Ad5-GUCY2C-PADRE phase I trial (which evaluated an Ad5-based vaccine), Ad5.F35-specific neutralizing antibody titers were substantially lower than Ad5-specific titers, with only 50% of patients possessing low anti-Ad5 titers compared to 90% with low anti-Ad5.F35 titers.
Tal Kan, Erik Feldman, Michael Timaner, Ziv Raviv, Shai Shen-Orr, Ami Aronheim, Yuval Shaked
Journal for ImmunoTherapy of Cancer 2020;8:e001010 (24 August 2020)
Interleukin (IL)-31, a proinflammatory cytokine from the IL-6 family, acts as an antiangiogenic agent and emerging data from mouse models lacking the IL-31 receptor hint at a role in regulation of type 2 inflammation. To characterize a potentially immunomodulatory role for the cytokine in breast cancer, Tal Kan and colleagues implanted mice with two different IL-31-expressing carcinoma cell lines: PyMT (a model for Luminal B breast carcinoma) and EMT6 (a model for triple negative breast cancer). Tumor growth rates were reduced for both subtypes, although the decrease was more pronounced for the PyMT model. Intratumoral granzyme B levels and CD8+ central memory T cell counts were elevated in the IL-31-expressing PyMT tumors, while the levels of CD4+CD25+ T cells and CD4+ effector memory T cells were reduced. Furthermore, fewer immunosuppressive M2 macrophages myeloid-derived suppressor cells (MDSCs) were present within tumors expressing IL-31, while proinflammatory M1 macrophage populations were increased. Although IL-31 had no apparent effect on the activation state or proliferation rate of isolated splenic CD8+ T cells in vitro, in co-culture experiments where MDSCs were present, treatment with the cytokine significantly increased the frequency of CD8+ T cells with central memory phenotype. In cultures of whole splenocytes, the addition of IL-31 resulted in inhibition of MDSC cell motility. IL-31-treated M2 macrophages secreted higher levels of factors associated with recruitment, activation, and survival of lymphocytes, as well as higher levels of Pentraxin 3, which inhibits metastasis. In mice harboring PyMT tumors and treated with a recombinant IL-31 bound to an IgG backbone, tumor growth was inhibited and significantly lower levels of intratumoral CD4+CD25+ T cells, tumor-associated macrophages and MDSCs were observed compared to in control IgG-treated mice.
Celine Boutros, Nathalie Chaput-Gras, Emilie Lanoy, Alicia Larive, Christine Mateus, Emilie Routier, Roger Sun, Yun Gan Tao, Christophe Massard, Rastilav Bahleda, Dominique Schwob, Nathalie Ibrahim, Rita Maria Khoury Abboud, Caroline Caramella, Andrea Lancia, Lydie Cassard, Severine Roy, J -C Soria, Caroline Robert, Eric Deutsch
Journal for ImmunoTherapy of Cancer 2020;8:e000627 (20 August 2020)
Preclinical models have demonstrated synergy between radiotherapy and anti-CTLA-4 checkpoint blockade. In the Mel-Ipi-Rx phase I study, Celine Boutros et al determined the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in checkpoint inhibitor naïve patients with metastatic melanoma. Using a 3+3 dose escalation design, 19 patients were treated with 9, 15, 18 and 24 Gy doses of radiotherapy combined with ipilimumab at 10 mg/kg every 3 weeks for four doses. Nine patients experienced Grade 3 adverse events, with the most common being colitis and hepatitis. A total of four patients experienced dose-limiting toxicities that led to permanent discontinuation of ipilimumab. The MTD for radiotherapy was determined to be 9 Gy. The objective response rate was 31%, with 2 complete responses, 3 partial responses and 7 cases of stable disease, for a clinical benefit rate of 75% at week 24. Response of non-irradiated lesions was numerically more representative of patient outcomes as compared to responses in irradiated lesions, but the number of patients was too low for statistical testing. Analysis of immune cells revealed significant increases in CD4+ T effector memory ICOS+CD4+ T cells at week 6. High fold changes in CD8+ T cell counts from baseline to week 4 was significantly associated with progression-free, but not overall survival. The findings point toward immune response biomarkers that could identify a subset of patients that may benefit from combination radio- and immunotherapy.
Siddharth Sheth, Chen Gao, Nancy Mueller, Natasha Angra, Ashok Gupta, Caroline Germa, Pablo Martinez, Jean-Charles Soria
Journal for ImmunoTherapy of Cancer 2020;8:e000650 (26 August 2020)
Select few studies have evaluated reinitiation of ipilimumab, pembrolizumab, or nivolumab in previously-treated patients, but data are sparse on potential clinical benefit with retreatment with anti-PD-L1 therapies. Siddharth Sheth and colleagues evaluated safety and efficacy of durvalumab retreatment in patients with advanced solid tumors who were taken off therapy at 1 year per study protocol and subsequently experienced disease progression. Among the 168 patients who completed 1 year of initial durvalumab therapy, 70 underwent retreatment, with 14 tumor types represented, most commonly non-small cell lung cancer, microsatellite instability (MSI-H) cancers, urothelial carcinoma, squamous cell carcinoma of the head and neck, and hepatocellular carcinoma. Patients with an objective response to initial durvalumab therapy experienced a longer time off treatment until disease progression compared with those without, but objective responses during initial treatment were not associated with objective responses or longer times to disease progression during retreatment. Median time to response was generally shorter with initial treatment compared with retreatment, but the median duration of responses were similar. The disease control rates and 12-month progression-free survival rates with retreatment were roughly half of those with initial therapy. Response rates, disease control rates, and median duration of responses were generally greater in patients with high PD-L1 expression than those with low or negative expression. No new safety signals were observed during retreatment. The findings support retreatment of patients who stop anti-PD-L1 therapy for reasons other than progression or toxicity.
Aung Naing, Joseph P Eder, Sarina A Piha-Paul, Claude Gimmi, Elizabeth Hussey, Sen Zhang, Vera Hildebrand, Vinayak Hosagrahara, Christina Habermehl, Jacques Moisan, Kyriakos P Papadopoulos
Journal for ImmunoTherapy of Cancer 2020;8:e000870 (24 August 2020)
Overexpression of IDO1 and TDO1—the enzymes that catalyze the first, rate-limiting step in the conversion of tryptophan to the immunosuppressive metabolite kynurenine—is associated with poor prognosis in several types of cancer. Aung Naing and colleagues report pre-clinical and first-in human phase I data on the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112, a first-in-class, orally administered, selective dual inhibitor of IDO1 and TDO2. In multiple mouse models of IDO1-expressing tumors, dose-dependent reductions in the kynurenine:tryptophan ratio were observed in the liver and plasma of mice after M4112 administration. For the phase I trial, 15 patients received M4112 at five dose levels. Inhibition of IDO1 in ex vivo stimulated blood was seen within four hours after M4112 across all doses tested. However, despite initial increases in plasma tryptophan levels after dosing, kynurenine levels returned to baseline levels by day 15 of cycle 1, leading to study discontinuation due to insufficient pharmacodynamic effect. The best overall response was stable disease in nine patients. One dose-limiting toxicity occurred: a case of grade 3 allergic dermatitis. Neither the maximum tolerated dose nor the recommended phase II dose were established. Although dual inhibition of IDO1 and TDO2 may be insufficient to provoke antitumor responses alone, the findings lay the groundwork for future studies investigating rational combinations with other immuno-oncology agents. In this regard, it is worth noting a recent report identifying interleukin-4-induced-1 (IL4I1) as a major aryl hydrocarbon receptor (AHR)-activating enzyme that is not inhibited by IDO1 inhibitors. IL4I1-mediated tryptophan catabolism, promoted AHR-driven cancer cell motility and suppressed adaptive immunity (Sadik A et al, Cell 2020, https://doi.org/10.1016/j.cell.2020.07.038).
Pedro Barata, Neeraj Agarwal, Roberto Nussenzveig, Benjamin Gerendash, Ellen Jaeger, Whitley Hatton, Elisa Ledet, Brian Lewis, Jodi Layton, Hani Babiker, Alan Bryce, Rohan Garje, Cy Stein, Lesli Kiedrowski, Philip Saylor, Oliver Sartor
Journal for ImmunoTherapy of Cancer 2020;8:e001065 (11 August 2020)
Checkpoint inhibitor therapy has demonstrated limited benefit to date for unselected metastatic castration-resistant prostate cancer (mCRPC). Based on the tissue-agnostic approval for pembrolizumab for the treatment of microsatellite instability high (MSI-H) tumors, Pedro Barata and colleagues used the commercially available next-generation sequencing assay Guardant360 to identify patients with mCRPC eligible for therapy based on analysis of cell-free DNA (cfDNA). Testing was performed for 460 patients with advanced prostate cancer across eight academic centers. Among the 14 patients with MSI-H metastatic prostate cancer, 9 were treated with pembrolizumab. Declines in prostate-specific antigen (PSA) of greater than 50% from baseline were observed in four patients after pembrolizumab therapy, with three achieving greater than 99% reductions. At data cut-off, four patients were still on therapy, while four patients discontinued pembrolizumab due to progressive disease and one due to SARS-CoV-2 infection. MSI-H was also detected in tumor tissue NGS for all three patients with available tissue, however, no germline genomic alterations were found in the two patients who underwent separate germline testing. The report supports the use of liquid biopsy to identify metastatic prostate cancer patients with MSI-H tumors for potential treatment with pembrolizumab.