JITC Digest May 2021


Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

Welcome to the latest edition of the JITC Digest. Astute readers have likely noticed that this month’s digest is debuting a new feature. In addition to the usual programming—exciting new publications in JITC—the digest will now also highlight popular papers from the journal archive.
This month, we have four original research articles that offer novel insight on one of our field’s most challenging obstacles: resistance to therapy. Addressing immunotherapy resistance is a priority for the field as a whole, and the Society for Immunotherapy of Cancer is spearheading efforts toward developing uniform clinical definitions of resistance as well as support the basic and translational research in order to understand and overcome the mechanistic underpinnings.
Barbara Manzanares-Martin and colleagues reveal a surprising association between genomic heterozygosity for the killer-cell immunoglobin-like receptor and overcoming KRAS mutation-mediated resistance to cetuximab.
Disease that develops resistance to anti-PD-1 therapies is often highly challenging to treat, but results from two early phase trials in this month’s digest may offer patients new options. Brendan D Curti et al show safety and promising efficacy with the combination of a novel galectin antagonist and pembrolizumab for melanoma and head and neck cancer. Intratumoral injection of the oncolytic poliovirus PVSRIPO led to complete regressions even in uninjected lesions in some patients with melanoma in a phase I trial reported by Georgia M Beasley et al.
Finally, Michael W Knitz and colleagues provide deep mechanistic characterization of the interplay between dendritic cells and regulatory T cells that causes head and neck cancers to remain stubbornly immunologically cold after radioimmunotherapy.
Be sure to browse this month’s highlight of classic papers as well as the new original research—perhaps perspective from the archives may help spark novel insight into a new finding or vice versa.
Best regards,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

JITC Editor Picks

Improving selection of patients with metastatic colorectal cancer to benefit from cetuximab based on KIR genotypes

Barbara Manzanares-Martin, Arancha Cebrián Aranda, Laura del Puerto-Nevado, Rafael González, Sonia Solanes, Maria Auxiliadora Gómez-España, Jesús García-Foncillas, Enrique Aranda

Journal for ImmunoTherapy of Cancer 2021;9:e001705 (8 April 2021)


As many as 36%–46% of patients with metastatic colorectal cancer (mCRC) have tumors harboring mutations in KRAS, which are a common resistance mechanism to epidermal growth factor receptor (EGFR)-targeting therapies such as cetuximab. Because cetuximab is on an IgG1 isotype backbone, however, it may also mediate anti-tumor immunity through antibody-dependent cellular cytotoxicity. Barbara Manzanares-Martin and colleagues show that heterozygosity for the killer-cell immunoglobin-like receptor (KIR) is associated with clinical benefit with cetuximab in patients with mCRC harboring KRAS mutations. In the cohort, which included 69 patients with histologically confirmed mCRC and KRAS alterations, positive EGFR expression, and Eastern Cooperative Oncology Group performance status 2 or less, longer progression-free survival at 12 months (PFS12) and overall survival (OS) were seen for those with both inhibitor and activator haplotypes compared to the group that was homozygous for either allele. Centromeric-enriched distribution of KIR loci was also associated with shorter PFS12 and OS. Notably, specific known KRAS codon 12 mutations (G12C, G12V, and G12D) with prognostic value were not associated with any significant differences in PFS12 or OS compared to all other mutations, nor was stratification by transitions and transversions. In multivariate analysis, stratification based on KIR genotype was independently predictive of better PFS12 (HR 2.16) and centromeric versus telomeric distribution was an independent predictor for improved PFS12 (HR 2.26) and OS (HR 1.93). The results provide rationale to test if stratification based on KIR genotype can guide therapy selection for patients with KRAS mutations.

Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor

Brendan D Curti, Yoshinobu Koguchi, Rom S Leidner, Annah S Rolig, Elizabeth R Sturgill, Zhaoyu Sun, Yaping Wu, Venkatesh Rajamanickam, Brady Bernard, Ian Hilgart-Martiszus, Christopher B Fountain, George Morris, Noriko Iwamoto, Takashi Shimada, ShuChing Chang, Peter G Traber, Eliezer Zomer, J Rex Horton, Harold Shlevin, William L Redmond

Journal for ImmunoTherapy of Cancer 2021;9:e002371  (9 April 2021)



Galectin-3 (Gal-3) is a secreted beta-galactoside binding protein that has been implicated in cancer progression and has immunosuppressive activities including promotion of M2-macrophage polarization and inhibition of T cell activation. Hypothesizing that Gal-3 blockade could enhance anti-tumor responses with anti-PD-1, Brendan D Curti et al performed a phase I dose escalation study of pembrolizumab plus the novel galectin antagonist belapectin in patients with advanced metastatic melanoma or squamous cell carcinoma of the head and neck (HNSCC). The objective response rate was 33% (2 out of 6) for patients with HNSCC and 50% (7 out of 14) for patients with melanoma, with two of the responders having prior disease progression on checkpoint blockade. The combination was well-tolerated, with no toxicities deemed related or probably related to belapectin and all of the toxicities deemed related to pembrolizumab being grade 1 or 2. Statistically significant increases in proliferating activated (Ki67+ ICOS+) effector memory CD4+ T cells and CD8+ T cells after treatment were observed in patients with responsive disease—significantly fewer total numbers and frequencies of monocytic myeloid-derived suppressor cells were also associated with response to the combination. Baseline percentages of circulating PD-1+ effector memory CD8+ T cells and proportions of Gal-3+ tumor cells predicted response and high pembrolizumab levels at day 43 (ie, lower clearance of the checkpoint inhibitor) correlated with improved progression-free survival. The study sets the stage for a randomized phase II trial of pembrolizumab plus belapectin to evaluate efficacy of the combination and further characterize immunological correlates of response.

Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma

Georgia M Beasley, Smita K Nair, Norma E Farrow, Karenia Landa, Maria Angelica Selim, Carol Ann Wiggs, Sin-Ho Jung, Darell D Bigner, Andrea True Kelly, Matthias Gromeier, April KS Salama
Journal for ImmunoTherapy of Cancer
2021;9:e002203 (19 April 2021)


CD155, the poliovirus entry receptor, is expressed by neoplastic cells in solid tumors as well as on all monocytic lineage antigen-presenting cells. Based on pre-clinical evidence that intratumoral delivery of oncolytic poliovirus not only elicits cytopathogenic damage to tumor cells but also produces sustained type I/III IFN dominant inflammation in the tumor microenvironment, Georgia M Beasley and colleagues enrolled 12 patients with unresectable melanoma onto an open-label phase I trial of intralesional injection of PVSRIPO, a live attenuated, type I poliovirus (Sabin vaccine platform) carrying an internal ribosomal entry site of human rhinovirus type 2. Of the 12 enrolled patients, 58% (n = 7) were considered to have primary resistance to anti-PD-1 therapy and 33% (n = 4) were considered to have secondary resistance, as defined per the Society for Immunotherapy of Cancer (SITC) taskforce consensus. Objective responses by immune-related response criteria (iRC) were achieved by four patients, all of whom received three injections of PVSRIPO. Pathological complete responses with no viable tumor detected in injected and non-injected lesions were seen in two patients. The eight patients who did not gain clinical benefit with PVSRIPO were taken off study early. PVSRIPO was well-tolerated with no serious adverse events or dose-limiting toxicities and the most commonly reported side effect being low-grade pruritus localized to the injection site. The favorable safety and initial efficacy reported in this trial supports further investigation of PVSRIPO either alone or in combination with checkpoint blockade for anti-PD-1 resistant melanoma.

Targeting resistance to radiation-immunotherapy in cold HNSCCs by modulating the Treg-dendritic cell axis

Michael W Knitz, Thomas E Bickett, Laurel B Darragh, Ayman J Oweida, Shilpa Bhatia, Benjamin Van Court, Shiv Bhuvane, Miles Piper, Jacob Gadwa, Adam C Mueller, Diemmy Nguyen, Varuna Nangia, Douglas G Osborne, Xiyuan Bai, Sarah E Ferrara, Mary-Keara Boss, Andrew Goodspeed, Matthew A Burchill, Beth A Jirón Tamburini, Edward D Chan, Curtis R Pickering, Eric T Clambey, Sana D Karam

Journal for ImmunoTherapy of Cancer 2021;9:e001955 (21 April 2021)



HPV-negative squamous cell carcinomas of the head and neck (HNSCC) are immunologically cold. Clinical trials aimed at harnessing radiotherapy (RT) to create an inflammatory intratumoral milieu and thus enhance responses to immunotherapy have yielded disappointing results. Michael W Knitz et al characterize a complex interplay between lymph node dendritic cell (DC) activation and Treg functionality contributing to RT resistance in murine models of immunologically cold HNSCC. The combination of RT and an optimized anti-CD25 that depletes not only peripheral but also intratumoral Tregs led to tumor eradication in the LY2 but not MOC2 model. Gene expression profiles showed differential expression of several Treg-associated coinhibitory markers 7 days after RT, including CTLA-4, PD-1, TIGIT, TIM3, LAG3, and GITR. Depletion of F4/80+ TAMs and Gr-1+ myeloid-derived suppressor cells did not enhance response to the combination of RT and anti-CD25. The addition of anti-CD137 agonism to RT and anti-CD25 led to enhanced CD103+ DC activation in tumor-draining lymph nodes with simultaneous Treg reprogramming to an effector phenotype with increased populations of cells positive for interferon gamma, tumor necrosis factor alpha, PI3K, phosphorylated AKT, and Eomes. Increasing the dose of RT to a hypofractionated 8 Gy x 5 regimen in combination with anti-CD25 and anti-CD137 led to tumor eradication. Interrogation of RNA sequencing and clinical datasets from patients with HNSCC confirmed elevated expression of CD137 in human Tregs as well as a significant benefit in disease-free survival associated with Treg-low gene signatures. The study highlights Treg plasticity—possibly identifying a new target to overcome resistance to radioimmunotherapy in HNSCC.

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Popular Archive Articles

The selections below represent some of the most popular content published in JITC over the past few years. Explore additional thematic content in JITC's Collections or access the rest of JITC's archives for a look at all the journal has to offer.

A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable

Alessio Cortellini, Melissa Bersanelli, Sebastiano Buti, Katia Cannita, Daniele Santini, Fabiana Perrone, Raffaele Giusti, Marcello Tiseo, Maria Michiara, Pietro Di Marino, Nicola Tinari, Michele De Tursi, Federica Zoratto, Enzo Veltri, Riccardo Marconcini, Francesco Malorgio, Marco Russano, Cecilia Anesi, Tea Zeppola, Marco Filetti, Paolo Marchetti, Andrea Botticelli, Gian Carlo Antonini Cappellini, Federica De Galitiis, Maria Giuseppa Vitale, Francesca Rastelli, Federica Pergolesi, Rossana Berardi, Silvia Rinaldi, Marianna Tudini, Rosa Rita Silva, Annagrazia Pireddu, Francesco Atzori, Rita Chiari, Biagio Ricciuti, Andrea De Giglio, Daniela Iacono, Alain Gelibter, Mario Alberto Occhipinti, Alessandro Parisi, Giampiero Porzio, Maria Concetta Fargnoli, Paolo Antonio Ascierto, Corrado Ficorella, Clara Natoli

Journal for ImmunoTherapy of Cancer 2019;7:57 (27 February 2019)

Exploring the emerging role of the microbiome in cancer immunotherapy

Jessica Fessler, Vyara Matson, Thomas F. Gajewski

Journal for ImmunoTherapy of Cancer 2019;7:108  (17 April 2019)


Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis

Hamzah Abu-Sbeih, Faisal S. Ali, Xuemei Wang, Niharika Mallepally, Ellie Chen, Mehmet Altan, Robert S. Bresalier, Aline Charabaty, Ramona Dadu, Amir Jazaeri, Bret Lashner, Yinghong Wang
Journal for ImmunoTherapy of Cancer
2019;7:93 (2 April 2019)

Dual targeting of TGF-beta and PD-L1 via a bifunctional anti-PD-L1/TGF-betaRII agent: status of preclinical and clinical advances

Hanne Lind, Sofia R Gameiro, Caroline Jochems, Renee N. Donahue, Julius Strauss, James L Gulley, Claudia Palena, Jeffrey Schlom

Journal for ImmunoTherapy of Cancer 2020;8:e000433 (19 February 2020)


The Society for Immunotherapy of Cancer perspective on regulation of interleukin-6 signaling in COVID-19-related systemic inflammatory response

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, Paolo Antonio Ascierto

Journal for ImmunoTherapy of Cancer 2020;8:e000930 (7 May 2020)

Position Article and Guidelines

SITC Members Receive 50 Percent Submission Discount in 2021

*As a way to thank the SITC members who work tirelessly to advance the science and improve the lives of cancer patients, SITC will provide members with a 50 percent discount on processing fees for all JITC articles accepted in 2021.