Letter from the Editor
Dear JITC Readers,
Welcome to the August edition of the JITC Digest. Many of our readers in the northern hemisphere may be using this time to take advantage of the last few weeks of summer before the academic year resumes. Hopefully you are applying sunscreen regularly if you are reading this edition of the digest at the beach or another idyllic locale.
Looking ahead, I’m thrilled to share the launch of JITC’s Peer Review Mentorship Program. You can find more details in this month’s special feature about this exciting new initiative to help train the next generation of reviewers who will help sustain the quality of our journal and the field as a whole for many years to come.
Our article highlights this month draw from the worlds of microbiology and mathematics—illustrating the power of very small biological entities and very big numbers to optimize immunological control of cancer.
Rebecca A. Bekker and colleagues offer a hypothesis paper proposing the use of mathematical approaches to conceptualize the effect of various immune and chemotherapies on the tumor immune microenvironment and tailor combination approaches on a per-patient basis.
In characterizing a vaccine strain of Mycobacterium tuberculosis as an intravesical treatment for bladder cancer, Eduardo Moreo et al elucidate the specific bacterial virulence factors and a requirement for host type 1 conventional dendritic cells for antitumor efficacy.
Teresa T. Nguyen and colleagues provide preclinical rationale for combination oncolytic virus therapy plus IDO inhibition for the treatment of recurrent glioma.
And finally, the first spatial mapping of the lung cancer microbiota is described by Abigail Wong-Rolle et al, who find bacteria to be enriched in tumor cells with an accompanying upregulation of genes involved in immune exclusion.
I hope you enjoy the articles in this month’s digest and I encourage early career professionals to consider applying to the Peer Review Mentorship Program.
Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer
JITC Editor Picks
Rebecca A Bekker, Mohammad U Zahid, Jennifer M Binning, Bryan Q Spring, Patrick Hwu, Shari Pilon-Thomas, Heiko Enderling
Journal for ImmunoTherapy of Cancer 2022;10:e005107(6 July 2022)
HYPOTHESIS
Summary:
Given the current lack of immune biomarkers that can explain why patients with tumors of similar clinical stage and molecular profiles may have disparate outcomes with immunotherapy, Rebecca A. Bekker and colleagues put forth a hypothesis that tools from mathematical oncology could be applied to predicting treatment response. Central to the hypothesis is the concept of an individual patient’s tumor-immune state, which includes the burden and aggressiveness of disease as well as the frequency and potency of tumor-specific immune effector cells. Using a reductionist model and borrowing from classical Lotka-Volterra predator/prey equations from the ecology field, distinct outcomes of immune escape and immune-mediated tumor control over time can be shown to be predicted by initial numbers of tumor and immune cells. Furthermore, the effects of cytotoxic therapy, adoptive cell therapy, and checkpoint blockade, among other treatments, can be conceptualized as agents that alter fundamental parameters of the tumor-immune state, which may enable the rational selection of combinations for individual patients. Of course, cancer is more complex than a homogeneous tumor cell population expressing a tumor-specific antigen and susceptible to elimination by cancer-specific immune effector cells. As such, the hypothesis concludes with a call to advance methodology for measurement of the tumor-immune state and emphasizes that with sufficient sophistication of inputs and models, the complex and dynamic interactions between cancer and the immune system could be rendered predictable.
Eduardo Moreo, Santiago Uranga, Ana Picó, Ana Belén Gómez, Denise Nardelli-Haefliger, Carlos del Fresno, Ingrid Murillo, Eugenia Puentes, Esteban Rodríguez, Mar Vales-Gómez, Julian Pardo, David Sancho, Carlos Martín, Nacho Aguilo
Journal for ImmunoTherapy of Cancer 2022;10:e004325(3 July 2022)
RESEARCH
Summary:
Intravesical administration of the live attenuated Mycobacterium bovis strain Bacillus Calmette-Guérin (BCG) has been the standard of care for intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) for several decades, yet the bacterial and host determinants of tumor rejection with this bacterial immunotherapy remain poorly understood. In characterizing the antitumor efficacy of an attenuated Mycobacterium tuberculosis strain currently being developed as a tuberculosis vaccine candidate in preclinical bladder cancer models, Eduardo Moreo and colleagues identify essential contributions of bacterial virulence factors and host type 1 conventional dendritic cells (cDC1s) to antitumor efficacy. Unlike BCG, the attenuated Mycobacterium tuberculosis strain MTBVAC retains intact loci encoding ESAT6 and CFP10 proteins, which are involved in epithelial attachment. In syngeneic MB49 bladder tumor-bearing mice, intravesical MTBVAC led to more robust colonization of the bladder and lymph nodes compared to BCG, with an accompanying roughly three-fold more mice surviving at the 70-day time point. ESAT6 and CFP10 were necessary for the colonization advantage for MTBVAC, as were host Rag1, interferon gamma, and perforin. MTBVAC led to an immune cell-mediated upregulation of MHC-I on tumor cells and enhanced effector functions for tumor epitope-specific cytotoxic lymphocytes. Intravesical MTBVAC was associated with migration of cDC1s to the bladder and presentation of tumor antigens by cDC1s in the tumor-draining lymph node. Correspondingly, the therapeutic efficacy of MTBVAC was abolished in mice lacking cDC1s. Strikingly, intravesical MTBVAC induced complete rejection of established tumors—a setting where BCG is ineffective—and the potency was further enhanced in combination with anti-PD-1. Given the ongoing BCG shortage, these preclinical findings provide rationale for further investigation of MTBVAC as an immunotherapeutic option.
Teresa T Nguyen, Dong Ho Shin, Sagar Sohoni, Sanjay K Singh, Yisel Rivera-Molina, Hong Jiang, Xuejun Fan, Joy Gumin, Frederick F Lang, Christopher Alvarez-Breckenridge, Filipa Godoy-Vitorino, Lisha Zhu, W Jim Zheng, Lijie Zhai, Erik Ladomersky, Kristen L Lauing, Marta M Alonso, Derek A Wainwright, Candelaria Gomez-Manzano, Juan Fueyo
Journal for ImmunoTherapy of Cancer 2022;10:e004495 (28 July 2022)
RESEARCH
Summary:
Oncolytic virotherapy has been reported to induce complete tumor regression in some patients with recurrent glioblastoma, however, immunosuppression in the microenvironment is a major hurdle limiting the efficacy of immunotherapy approaches in this setting. Teresa T Nguyen and colleagues demonstrate that combination oncolytic virus therapy and IDO inhibition reshape the tumor immune microenvironment and prolong survival compared to either monotherapy in murine models of glioma. Intratumoral administration of an OX40-ligand carrying adenovirus, Delta-24-RGDOX (DNX-2440), led to significant upregulation of IDO-related transcripts and an associated increase in the IDO-produced metabolite kynurenine in the tumor microenvironment in two glioma models. In vitro, conditioned media from Delta-24-RGDOX-infected glioma cell line led to nuclear translocation of the aryl hydrocarbon receptor (AhR) and activation of AhR-responsive promoters, consistent with viral induction of an IDO-mediated immunosuppressive signaling cascade. In the GL261-5 glioma model, combination Delta-24-RGDOX infection with IDO inhibition via 1MT prolonged survival in treated mice by roughly threefold compared with either monotherapy and more than doubled the rate of long-term survival observed with oncolytic virotherapy alone. Mice treated with the combination rejected tumors upon rechallenge, supporting the establishment of a memory response against glioma antigens. CD4+ T cells were required for efficacy with the combination, and bulk RNA sequencing revealed distinct signatures between untreated gliomas and tumors treated with IDO inhibition alone, Delta-24-RGDOX alone, or the combination, specifically in expression of genes related to immune checkpoint regulators, inflammation-related cytokines, Toll-like receptors 7 and 9, and components of the stimulator of interferon genes (STING) pathway. These results support evaluation of IDO inhibition to potentiate oncolytic virus approaches in future trials.
Abigail Wong-Rolle, Qiang Dong, Yunhua Zhu, Prajan Divakar, Jyh Liang Hor, Noemi Kedei, Madeline Wong, Desiree Tillo, Elizabeth A Conner, Arun Rajan, David S Schrump, Chengcheng Jin, Ronald N Germain, Chen Zhao
Journal for ImmunoTherapy of Cancer 2022;10:e004698 (6 July 2022)
RESEARCH
Summary:
While the gut microbiome is now recognized as an important determinant of cancer development, prognosis, and response to immunotherapy, little is known about the interactions between microbes, tumor cells, stroma, and healthy tissue in lung cancer. Using a novel NanoString spatial transcriptomics analysis, Abigail Wong-Rolle et al describe enrichment for internalization of bacteria in lung cancer tumor cells with an associated upregulation of genes involved in immune exclusion. Probes targeting bacterial 16S rRNA, fungal 28S rRNA, CMV UL38 transcripts, and RNA products from 1,800 human genes involved in oncogenic and immune pathways were used to assay formalin-fixed paraffin embedded samples from 12 patients with early stage lung cancer without clinically detectable pulmonary infections or antibiotic use who were enrolled in two different clinical trials. Across samples, fungal and CMV signals significantly above background were not detected. The bacterial burden in tumor cells was up to two logs higher than that in normal tissue, stroma, macrophages, neutrophils, T cells, and B cells, as well as tertiary lymphoid structures. In the one patient sample where small airway tissue was included, a high bacterial burden was observed in the airway, hinting at a route of introduction. Notably, expression of genes involved in beta catenin signaling, hypoxia, and angiogenesis were positively correlated with bacterial burden in tumor cells. Although the presence of an EGFR driver mutation showed no significant interaction with bacterial burden, samples from smokers had significantly fewer bacteria, possibly due to antimicrobial effects of tobacco smoke. While this study did not provide taxa-level resolution on the bacteria present nor information linking burden to outcomes, the findings set the stage for future inquiry into the interplay between the lung microbiota and the immune system in lung cancer.
Other Recent JITC Articles
Peer Review Mentorship Program
JITC is proud to announce the new JITC Peer Review Mentorship Program, designed to help train the next generation on the general practices of scientific peer review. Applications to serve as a mentee are now being collected through September 14th. Early career professionals with limited or no peer reviewing experience are encouraged to apply. Successful applicants will be paired with a senior leader and review one manuscript approximately every six weeks from January–October 2023.
More details, including key dates and the application form, are found on the reviewer webpage.
Apply today!
From the Vault
Throughout 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 Clinical Trials Monitor section in JITC over the years.
Explore additional thematic content in JITC's Collections and access the most popular content from the past few years for a deeper look at all the journal has to offer.
Claud Grigg and Naiyer A Rizvi
Journal for ImmunoTherapy of Cancer 2016;4:48 (16 August 2016)
CLINICAL TRIALS MONITOR
Josephine Kang, Sandra Demaria and Silvia Formenti
Journal for ImmunoTherapy of Cancer 2016;4:51 (20 September 2016)
CLINICAL TRIALS MONITOR
Hasan Rehman, Ann W Silk, Michael P Kane and Howard L Kaufman
Journal for ImmunoTherapy of Cancer 2016;4:53 (20 September 2016)
CLINICAL TRIALS MONITOR
Robert D Leone and Leisha A Emens
Journal for ImmunoTherapy of Cancer 2018;6:57 (18 June 2018)
CLINICAL TRIALS MONITOR
David G DeNardo, Anna Galkin, Jakob Dupont, Lei Zhou and Johanna Bendell
Journal for ImmunoTherapy of Cancer 2021;9:e003005 (27 August 2021)
CLINICAL TRIALS MONITOR
Carey K Anders, G Woodcock, Amanda E D Van Swearingen, Dominic T Moore, Maria J Sambade, Sonia Laurie, Alexander Robeson, Oleg Kolupaev, Luz A Cuaboy, Amy L Garrett, Karen McKinnon, Kristen Cowens, Dante Bortone, Benjamin C Calhoun, Alec D Wilkinson, Lisa Carey, Trevor Jolly, Hyman Muss, Katherine Reeder-Hayes, Rebecca Kaltman, Rachel Jankowitz, Vinay Gudena, Oludamilola Olajide, Charles Perou, E Claire Dees, Benjamin G Vincent and Jonathan S Serody
Journal for ImmunoTherapy of Cancer 2022;10:e003427 (4 February 2022)
CLINICAL TRIALS MONITOR
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.