JITC Editor Picks
Fernanda I Arnaldez, Steven J O'Day, Charles G Drake, Bernard A Fox, Bingqing Fu, Walter J Urba, Vincenzo Montesarchio, Jeffrey S Weber, Haiming Wei, Jon M Wigginton and Paolo Antonio Ascierto
Journal for ImmunoTherapy of Cancer 2020;8:e000930 (7 May 2020)
Initial experience from the COVID-19 outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. Drawing on extensive experience administering immune-modulating therapies, SITC identified potential alternatives to anti-IL-6 including modulation of IL-1, GM-CSF and TNF alpha as well as inhibition of JAK/STAT signaling.
Janis M Taube, Guray Akturk, Michael Angelo, Elizabeth L Engle, Sacha Gnjatic, Shirley Greenbaum, Noah F Greenwald, Cyrus V Hedvat, Travis J Hollmann, Jonathan Juco, Edwin R Parra, Marlon C Rebelatto, David L Rimm, Jaime Rodriguez-Canales, Kurt A Schalper, Edward C Stack, Cláudia S Ferreira, Konstanty Korski, Ana Lako, Scott J Rodig, Emanuel Schenck, Keith E Steele, Michael J Surace, Michael T Tetzlaff, Katharina von Loga, Ignacio I Wistuba and Carlo B Bifulco on behalf of the Society for Immunotherapy of Cancer (SITC) Pathology Task Force.
Journal for ImmunoTherapy of Cancer 2020;8:e000155 (15 May 2020)
Multiplex immunohistochemistry and immunofluorescence technologies are becoming standard tools for immunotherapy biomarker studies and are likely to enter routine clinical practice in the near future. In order to establish best practice guidelines for the optimization and validation of multiplex assays, SITC convened a task force of pathologists and laboratory leaders from academic centers as well as experts from pharmaceutical and diagnostic companies to discuss key considerations for ensuring that outputs are robust and comparable across institutions and platforms.
Seongmin Cho, Sang Bum Kim, Youngjin Lee, Ee Chan Song, Uijoo Kim, Hyeong Yun Kim, Ji Hun Suh, Peter C Goughnour, YounHa Kim, Ina Yoon, Na Young Shin, Doyeun Kim, Il-Kyu Kim, Chang-Yuil Kang, Song Yee Jang, Myung Hee Kim and Sunghoon Kim
Journal for ImmunoTherapy of Cancer 2020;8:e000277 (26 May 2020)
The development of Toll-like receptor (TLR) ligands for immunotherapy has been hindered by rapid systemic toxicity with these agents. Seongmin Cho and colleagues identify an endogenous and novel TLR2/6 ligand embedded in the catalytic region of human cysteinyl-tRNA synthetase 1 (CARS1) that can act as an adjuvant to activate anti-tumor immune responses. Cultured human colon cancer cells secreted CARS1 under conditions of endoplasmic reticulum and inflammatory stress but not after treatment with growth factors and cytokines. Immunofluorescence and flow cytometry revealed preferential binding of CARS1 to macrophages and monocytes, but not B or T cells. A unique domain (UNE-C1) inserted into the catalytic region of CARS1 was necessary and sufficient for dendritic cell activation. Bone-marrow derived cells upregulated proinflammatory genes including il-6, nos2, il-12, cd40, cd80, and cd86 upon UNE-C1 treatment. In vivo, UNE-C1 increased antigen presentation on non-plasmacytoid dendritic cells. Immunization with OVA antigen combined with UNE-C1 produced specific anti-OVA antibodies and induced functional antigen-specific CD8+ T cells. In mouse models, a combination of vaccination with tumor antigen and UNE-C1 with anti-CTLA-4 treatment significantly improved survival. Importantly, UNE-C1 did not induce systemic toxicity in vivo, unlike known TLR agonists, which caused a significant release of inflammatory cytokines in treated mice. The findings suggest the UNE-C1 domain can be developed as an immunoadjuvant with checkpoint inhibitors or cancer antigens to boost antitumor immunity.
Victor H Engelhard, Rebecca C Obeng, Kara L Cummings, Gina R Petroni, Angela L Ambakhutwala, Kimberly A Chianese-Bullock, Kelly T Smith, Amanda Lulu, Nikole Varhegyi, Mark E Smolkin, Paisley Myers, Keira E Mahoney, Jeffrey Shabanowitz, Nico Buettner, Emily H Hall, Kathleen Haden, Mark Cobbold, Donald F Hunt, Geoffrey Weiss, Elizabeth Gaughan and Craig L Slingluff, Jr
Journal for ImmunoTherapy of Cancer 2020;8:e000262 (7 May 2020)
Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens that are promising targets for cancer vaccines. In prior studies, an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) was identified as one such neoantigen. Here, Victor H Engelhard and colleagues identify and characterize a second phosphopeptide, from breast cancer antiestrogen resistance 3 (BCAR3), and evaluate safety and immunogenicity of a novel immunotherapeutic vaccine comprising phosphorylated peptides in a first-in-human trial. They show that a phosphopeptide of BCAR3 modified by substitution of V for L at residue 134 (for higher affinity for HLA-A*0201) called pBCAR3(V)126-134 induced antigen specific human T cells in vitro and was immunogenic in vivo in HLA-A2 transgenic mice. The phosphopeptide vaccine candidates were evaluated in an open-label, pilot, proof-of-concept study that enrolled 15 patients who had undergone surgical resection of stage II, III or IV melanoma to one of three arms: Arm A (3 patients) received pBCAR3126-134 only; Arm B (3 patients) received pIRS21097-1105 only; and Arm C (9 patients) was vaccinated with pBCAR3126-134 + pIRS21097-1105. All patients had grade 1 and 2 adverse events and all developed grade 2 vaccine injection site reactions. There were no treatment-related toxicities of grade 3 or greater. Overall 6 of 15 patients (40%) had a T cell response to either or both of the vaccine peptides with the majority of responses detected at a single time point, typically at weeks 3, 5 or 8. The estimated 4-year overall survival was 80% and the median disease-free survival was just over 1.0 year.
Thomas LaSalle, Emily E Austin, Grant Rigney, Eric Wehrenberg-Klee, Sarah Nesti, Benjamin Larimer and Umar Mahmood
Journal for ImmunoTherapy of Cancer 2020;8:e000291 (26 May 2020)
Overall survival as an endpoint does not reflect the nuanced biology that may occur during an anti-tumor response. Using a novel PET agent that non-invasively quantifies granzyme B release in tumors, Thomas LaSalle and colleagues measured immune cell activation in tumors during checkpoint inhibitor therapies and identified cell types and cytokines that correlated with response to treatment. In murine MC38 tumors, which are mis-match repair deficient and immunologically "hot," early and robust granzyme B activity was detectable by PET, whereas the magnitude of the response was smaller in CT26 tumors, which are microsatellite stable. Across both tumors, granzyme B PET signal was negatively correlated with inactive T cells. Certain cytokines, such as tumor necrosis factor alpha, and macrophage inflammatory protein 1 beta (CCL4), were correlated with granzyme B response when found in both CT26 and MC38. However, these cytokines negatively corresponded with granzyme B in the lymph nodes, emphasizing the role tissue compartmentalization plays in the response. Intriguingly, eotaxin, which attracts eosinophils, was also correlated with response across both tumor types. Other cytokines, including IL-6, demonstrated distinct correlation patterns between MC38 and CT26 tumors and lymph nodes. The data provide proof of concept that granzyme B PET signal may help identify mechanisms of response to immunotherapy across a range of immunogenic tumor microenvironments
Jessica Roelands, Wouter Hendrickx, Gabriele Zoppoli, Raghvendra Mall, Mohamad Saad, Kyle Halliwill, Giuseppe Curigliano, Darawan Rinchai, Julie Decock, Lucia G Delogu, Tolga Turan, Josue Samayoa, Lotfi Chouchane, Alberto Ballestrero, Ena Wang, Pascal Finetti, Francois Bertucci, Lance D Miller, Jerome Galon, Francesco M Marincola, Peter J K Kuppen, Michele Ceccarelli, and Davide Bedognetti
Journal for ImmunoTherapy of Cancer 2020;8:e000617 (5 May 2020)
Pre-existing intratumoral anti-tumor T helper 1 (Th-1) immune responses have been linked to favorable outcomes with immunotherapy, but not all immunologically "hot" cancers respond to treatment. Building upon a previously defined gene expression signature called the Immunologic Constant of Rejection (ICR), Jessica Roelands and colleagues demonstrate that cancer-specific pathways modulate the prognostic power of favorable intratumoral immune responses. In a pan-tumor analysis of data from The Cancer Genome Atlas encompassing 31 different histologies from 9282 patients, high expression of the ICR signature was associated with significant survival benefit for some cancer types including breast invasive carcinoma, skin cutaneous melanoma, uterine corpus endometrial carcinoma, and sarcoma while being linked to significantly reduced OS in other cancer types such as uveal melanoma, low grade glioma, pancreatic adenocarcinoma and kidney renal clear cell carcinoma. ICR score was associated with significantly improved survival independent of mutation rate in cancers with increased proliferation and independent of proliferation in cancer with increased mutation rates. Notably, ICR scores were inversely correlated with expression of oncogenic pathway genes such as WNT-beta catenin signaling, AMPK signaling, telomerase extension, and Notch and Hedgehog signaling. Analysis of samples from melanoma patients treated with checkpoint inhibitors in the Van Allen melanoma dataset revealed association of high ICR scores pretreatment with survival only for samples with high proliferation scores. Conversely, ICR scores were only associated with survival in samples with low TGF beta expression. The results suggest that in tumors with high mutation burdens and/or high proliferation, ICR captures a true protective anti-tumor immune response, whereas in tumors dominated by cancer signaling ICR captures bystander or heavily suppressed immune infiltration with no protective effect.
John P Lynes, Anthony K Nwankwo, Hannah P Sur, Victoria E Sanchez, Kwadwo A Sarpong, Oluwatobi I Ariyo, Gifty A Dominah and Edjah K Nduom
Journal for ImmunoTherapy of Cancer 2020;8:e000348 (30 May 2020)
Glioblastoma is known for exceptionally poor median survival and high recurrence rate with few treatment options. A highly immunosuppressive microenvironment along with profound intratumoral molecular heterogeneity pose particular challenges for the identification of actionable targets and biomarkers for response to treatment in the glioblastoma disease setting. In a timely review, John P Lynes and colleagues provide an overview of current efforts toward immunophenotyping glioblastoma as well as establishing the utility of cytokines, immune checkpoints and genetic aberrations as biomarkers for response to treatment. By providing an overview of newer non-invasive imaging and sampling methods and advocating for strategic stratification in clinical trial design, the review offers a perspective on the best path forward to identifying biomarkers that will aid in identifying patients with GBM who will most likely benefit from immunotherapy treatment regimens.