JITC Digest July 2022


Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

Welcome to the latest edition of the JITC Digest. This month we are excited to spotlight our new Imaging and Immunotherapy review series, edited by Elisabeth GE de Vries and Lawrence H Schwartz. This timely review series features discussion on novel emerging imaging strategies, innovative approaches to the analysis of conventional modalities such as artificial intelligence and radiomics, and special considerations for radiotherapy, immunotherapy, and imaging. You can read the introductory editorial to the series as well as the first few reviews at the collection page on the JITC site. Check back throughout 2022 for more publications.

Our original research article highlight this month includes four exciting papers that make progress toward overcoming longstanding challenges in our field: eliciting systemic immune responses to local therapy and serum-based biomarkers for tumor response. 

Robert B Rebhun and colleagues report a clinical benefit rate of 39% with minimal systemic toxicity in a first-in-canine phase I clinical trial evaluating inhaled recombinant human IL-15 for the treatment of spontaneous melanoma or osteosarcoma in companion dogs. 

Regression of untreated lesions in murine melanoma models with local injection of a hydrogel carrying a lysate of the bacterial immunotherapy Mycobacterium bovis Bacillus Calmette-Guérin is described by Mirela Kremenovic et al.

An almost 80% overall response rate to checkpoint blockade in pancreatic ductal adenocarcinoma identified as microsatellite instability-high through ctDNA analysis is observed in a retrospective analysis by Sakti Chakrabarti and colleagues. 

Michal Harel et al leverage machine learning and longitudinal plasma proteomic profiling to identify a signature based on age, sex, and on-treatment serum levels of CXCL18 and CXCL10 to predict benefit with anti-PD-1 in non-small cell lung cancer. 

If you’re looking for more reading material, this month’s selections from JITC’s archives include some of the top case reports and commentary/editorials over the years.


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

JITC Editor Picks

Inhaled recombinant human IL-15 in dogs with naturally occurring pulmonary metastases from osteosarcoma or melanoma: a phase 1 study of clinical activity and correlates of response

Robert B Rebhun, Daniel York, Sylvia Margret Cruz, Sean J Judge, Aryana M Razmara, Lauren E Farley, Rachel V Brady, Eric G Johnson, Jenna H Burton, Jennifer Willcox, Luke A Wittenburg, Kevin Woolard, Cordelia Dunai, Susan L Stewart, Ellen E Sparger, Sita S Withers, Alicia A Gingrich, Katherine A Skorupski, Sami Al-Nadaf, Amandine T LeJeune, William TN Culp, William J Murphy, Michael S Kent, Robert J Canter
Journal for ImmunoTherapy of Cancer 2022;10:e004493 (9 June 2022)
Cytokine therapy with IL-15 has yielded disappointing results in clinical trials, with stable disease as the most common best response and high rates of systemic toxicity. Inhalation of cytokines limits systemic exposure and potential toxicity while allowing for direct delivery of therapy to the lungs, motivating Robert B Rebhun and colleagues to perform a first-in-dog phase I clinical trial evaluating inhaled recombinant human IL-15 in companion canines with melanoma or osteosarcoma. The primary endpoints were safety, dose-limiting toxicities, and maximum tolerated dose with secondary objectives including response rate, progression-free survival, overall survival, and correlative studies. A total of 21 dogs were enrolled: 11 with melanoma and 10 with osteosarcoma. At the initial dose level of 10 micrograms, no fevers, hypotension or other abnormalities were observed and the most frequently reported side effect was coughing. No dose-limiting toxicities were observed until the fifth dose level, at which point clinically evident necrosis or abscessation of confirmed metastatic melanoma was observed in the lymph nodes of two of six dogs. The maximum tolerated dose and recommended phase II dose was found to be 50 micrograms twice daily for 14 days. Among the 18 evaluable dogs, the overall clinical benefit rate was 39% including 1 complete response lasting more than 1 year, 1 partial response with resolution of multiple lesions, and 5 cases of stable disease. Median survival from the first treatment was 113.5 (range 34–407) and 82.5 (range 36–655) days for dogs with melanoma and osteosarcoma, respectively. Serum levels of IL-15 after inhalation were in the picomolar range, remaining relatively stable for 6 hours after treatment with a peak at the 4 hour time-point. No association was observed between response to treatment and plasma levels of endogenous cytokines. Lower baseline absolute lymphocyte counts and increased cytoxiticy of peripheral blood monocuclear cells post-treatment were statistically significantly associated with response. These data provide rationale for additional trials of inhaled cytokine therapy in canine and human patients. 

BCG hydrogel promotes CTSS-mediated antigen processing and presentation, thereby suppressing metastasis and prolonging survival in melanoma

Mirela Kremenovic, Alfred A Chan, Bing Feng, Lukas Bäriswyl, Steve Robatel, Thomas Gruber, Li Tang, Delphine J Lee, Mirjam Schenk
Journal for ImmunoTherapy of Cancer 2022;10:e004493 (22 June 2022)
Intralesional administration of the live bacterial strain Mycobacterium bovis Bacillus Calmette-Guérin (BCG) has been known to induce regression of injected melanoma since the 1970s, however, responses in distal lesions are rare. Reasoning that sustained delivery of pathogen-associated molecular patterns might induce proinflammatory tumor microenvironment capable of generating systemic responses, Mirela Kremenovic et al developed a novel BCG lysate for loading into a thermosensitive hydrogel. The BCG lysate led to more pronounced reduction in tumor growth than live BCG in murine B16F10 melanoma models. Tumors injected with lysate had high frequencies of infiltrating CD8+ and CD4+ T cells, natural killer cells, dendritic cells, and tumor-associated M1 macrophages, as well as elevated levels of proinflammatory cytokines, CXCR2-binding cytokines, and growth factors with an accompanying shift in gene expression profile toward an immune-inflamed tumor microenvironment. Notably, injection of BCG lysate-loaded hydrogel not only led to similar profiles of effector cells and macrophages in the treated tumors as lysate alone but also increased lymphocytic infiltration in untreated tumors on the contralateral flank. BCG hydrogel injection prolonged survival of treated mice by 24% in the B16F10 melanoma model and suppressed the development of pulmonary metastases in MC38 tumor models. Injection of BCG hydrogel led to significant upregulation of genes involved in antigen processing and presentation including several cathepsins, response to interferon gamma, and positive regulation of leukocyte chemotaxis by bulk tumor RNA sequencing as well as an increase in infiltrating T cell receptor diversity and concomitant decreased clonality. In the tumor-draining lymph nodes, increases in antigen-presenting cells, dendritic cells, CD4+ and CD8+ T cells with a decrease in naïve T cells were also seen. These findings suggest that hydrogel delivery of BCG lysate is capable of inducing systemic anti-tumor immune responses through a mechanism involving enhanced antigen processing and presentation. 

Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer

Sakti Chakrabarti, Leslie Bucheit, Jason Scott Starr, Racquel Innis-Shelton, Ardaman Shergill, Hiba Dada, Regina Resta, Stephanie Wagner, Naomi Fei, Pashtoon Murtaza Kasi
Journal for ImmunoTherapy of Cancer 2022;10:e004493 (16 June 2022)
Tumors with high microsatellite instability (MSI-H) have excellent responses to checkpoint inhibition, however, tissue availability is often a barrier to genomic profiling. Building on reports of concordance between tissue- and circulating tumor DNA (ctDNA)-based measurements of MSI-H status, Sakti Chakrabarti et al retrospectively demonstrate a 77% overall response rate to checkpoint blockade for pancreatic cancer found to be MSI-H by liquid biopsy. Out of 6,000 patients with pancreatic ductal adenocarcinoma who underwent ctDNA profiling using the Guardant G360 74-gene panel, 52 were identified as MSI-H and clinical outcome data were available for 10, with 9 receiving ICI therapy. Among the six patients for whom both liquid and tumor biopsy results were available, only one case of non-concordance between ctDNA and tissue MSI-H testing was observed. Notably, the one tumor that was determined to be proficient in mismatch repair (the most common driver of microsatellite instability) by immunohistochemistry yet MSI-H by ctDNA analysis had a pathologic complete response to neoadjuvant anti-PD-1 plus anti-CTLA-4. Although small and retrospective, this analysis provides proof-of-concept for using validated ctDNA assays for identifying patients eligible for checkpoint blockade treatment through the tissue-agnostic indication for MSI-H tumors.

Longitudinal plasma proteomic profiling of patients with non-small cell lung cancer undergoing immune checkpoint blockade

Michal Harel, Coren Lahav, Eyal Jacob, Nili Dahan, Itamar Sela, Yehonatan Elon, Shani Raveh Shoval, Galit Yahalom, Iris Kamer, Alona Zer, Ofer Sharon, David P Carbone, Adam P Dicker, Jair Bar, Yuval Shaked
Journal for ImmunoTherapy of Cancer 2022;10:e004493 (19 June 2022)
Tumor-intrinsic biomarkers such as mutational burden and PD-L1 expression have limited predictive power for benefit with checkpoint blockade and current requirements for biopsy tissue for evaluation of these biomarkers is an obstacle to capturing tumor heterogeneity as well as changes that occur during treatment. Using pre- and on-treatment plasma proteomic profiling of roughly 800 proteins combined with machine learning approaches, Michal Harel and colleagues identify a signature to predict response to anti-PD-(L)1 based therapy for patients with non-small cell lung cancer (NSCLC) based on age, sex, and on-treatment serum levels of CXCL18 and CXCL10. A retrospective cohort of 143 patients with NSCLC were included in the analysis, of whom 70 had no clinical benefit with checkpoint inhibitor-based treatment and 73 benefited from therapy, defined as stable disease, partial response, or complete response at 3 months on-treatment by RECIST criteria. The four-parameter signature had an area under the receiver operating characteristic curve of 0.79. Interestingly, although the vast majority of the patients received anti-PD-1 monotherapy, the predictive value of the signature decreased when the 12 patients who were treated with anti-PD-1 in combination with chemotherapy were excluded from the model. Clustering based on overall plasma proteomic profiles pre- and on-treatment revealed three distinct groups, each characterized by unique clinical features and enriched for response or non-response to therapy. Elevated levels of several neutrophil-associated proteins on-treatment were associated with lack of benefit with therapy, including CXCL8, as well as IL-6, PILRA, TNFRSF21, PLAUR, CDH3, GOLM1, GRO (CXCL1/CXCL2/CXCL3), SDC1, and CXCL10. This study supports further development of serum-based biomarkers to capture dynamic changes in immune cell responses to tumors during treatment and predict benefit with immunotherapy. 

View other articles from this issue

Imaging and Immunotherapy Review Series

JITC is proud to announce the first publications in a new series of review articles, “Imaging and Immunotherapy.” Authored by leading voices from a multitude of backgrounds, including oncologists, imaging scientists, and radiologists, this series explores novel imaging strategies, new approaches to conventional imaging – including the use of artificial intelligence, radiomics, and MRI – and special considerations for radiotherapy, immunotherapy, and imaging.
Comprised of several authoritative reviews, and edited by Guest Editors Elisabeth GE de Vries, MD, PhD and Lawrence H Schwartz, MD, this JITC series illustrates the multidisciplinary approach vital to the use of imaging for immunotherapy as well as challenges to be overcome for new imaging methods to be implemented into daily use.
Check the collection throughout 2022 for new publications. 

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.

COVID-19 and immune checkpoint inhibitors: initial considerations

Ryan J Sullivan, Douglas B Johnson, Brian I Rini, Tomas G Neilan, Christine M Lovly, Javid J Moslehi, Kerry L Reynolds
Journal for ImmunoTherapy of Cancer 2020;8:e000933 (19 May 2020)

Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy

John Haanen, Marc Ernstoff, Yinghong Wang, Alexander Menzies, Igor Puzanov, Petros Grivas, James Larkin, Solange Peters, John Thompson, Michel Obeid
Journal for ImmunoTherapy of Cancer 2020;8:e000604 (12 June 2020)

SARS-CoV-2 infection in immunocompromised patients: humoral versus cell-mediated immunity

Jia Wei, Jianping Zhao, Meifang Han, Fankai Meng, Jianfeng Zhou
Journal for ImmunoTherapy of Cancer 2020;8:e000862 (29 July 2020)

Outcomes and biomarker analyses among patients with COVID-19 treated with interleukin 6 (IL-6) receptor antagonist sarilumab at a single institution in Italy

Vincenzo Montesarchio, Roberto Parrella, Chiara Iommelli, Antonella Bianco, Elio Manzillo, Fiorentino Fraganza, Cristiana Palumbo, Gaetano Rea, Patrizia Murino, Rosanna De Rosa, Luigi Atripaldi, Maurizio D’Abbraccio, Marcello Curvietto, Domenico Mallardo, Egidio Celentano, Antonio Maria Grimaldi, Marco Palla, Claudia Trojaniello, Maria Grazia Vitale, Samuel Lewis Million-Weaver, Paolo Antonio Ascierto
Journal for ImmunoTherapy of Cancer 2020;8:e001089 (11 August 2020)

Spontaneous tumor regression following COVID-19 vaccination

Luana Guimaraes de Sousa, Daniel J McGrail, Kaiyi Li, Mario L Marques-Piubelli, Cipriano Gonzalez, Hui Dai, Sammy Ferri-Borgogno, Myrna Godoy, Jared Burks, Shiaw-Yih Lin, Diana Bell, Renata Ferrarotto
Journal for ImmunoTherapy of Cancer 2022;10:e004371 (3 March 2022)

From the Vault

JITC-Anniversary-Small_2228301.jpgThroughout the journal’s celebratory 10th Anniversary year, this From the Vault special feature will highlight influential papers covering the wide variety of content the journal has published to advance the field. This month’s From the Vault takes a look at some of the top papers from the Case Reports and Commentary/Editorials sections in JITC over the years. 

Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma

Heinz Läubli, Cathrin Balmelli, Matthias Bossard, Otmar Pfister, Kathrin Glatz, Alfred Zippelius
Journal for ImmunoTherapy of Cancer 2015;3:11 (21 April 2015)

Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy

Lucie Heinzerling, Patrick A. Ott, F. Stephen Hodi, Aliya N. Husain, Azadeh Tajmir-Riahi, Hussein Tawbi, Matthias Pauschinger, Thomas F. Gajewski, Evan J. Lipson, Jason J. Luke
Journal for ImmunoTherapy of Cancer 2016;4:50 (16 August 2016)

High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors
Saman Maleki Vareki

Journal for ImmunoTherapy of Cancer 2018;6:157 (27 December 2018)

SITC Members Receive a 50 Percent Discount on Article Processing Charges in 2022
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 article processing fees for all JITC articles accepted in 2022.
Become a SITC Member Today!

JITC also offers waivers for the APC (100% discount of the APC) where all authors are based in low-income countries (see policy). Requests for waivers must be made prior to submission. For additional information regarding these discounts, as well as institutional arrangements, view the journal's APC policy. Additional questions may be directed to JITCEditor@sitcancer.org.