JITC Digest July 2019

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Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

In the July edition of the JITC Digest, I would like to draw attention to the following articles. First, "Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec (T-VEC) versus granulocyte-macrophage colony-stimulating factor in unresectable stage III–IV melanoma" by Robert H. I. Andtbacka et al. reports the final analysis of OS, objective response and complete responders in the OPTiM trial performed 3 years after the last patient was randomized. Compared to GM-CSF, T-VEC resulted in durable CR rates associated with prolonged survival, most notably in patients with early metastatic melanoma (stage IIIB–IVM1a).

Next, the research article entitled "DNA damage repair gene mutations and their association with tumor immune regulatory gene expression in muscle invasive bladder cancer subtypes," by Thiago Vidotto et al. investigated the pre-treatment immune landscape for patients with muscle invasive urothelial cancer (MIUC) using the Cibersort tools. Through correlation of immune regulatory gene expression profiles from the TCGA, this study tests the hypothesis that pre-treatment immune contexture and subsequent response of MIUC is dictated by cancer cell intrinsic events such as DDR deficiency. Results suggest a potential co-activation of multiple compensatory immune checkpoint pathways in pre-treatment MIUC, and warrant further development of combined biomarker and immunomodulatory treatment approaches in UC.

Furthermore, the article, "PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8+ T lymphocytes," by Jesús Ogando et al. analyzed gene expression profiles of human CD8+ T cells in conditions that mimic simultaneous engagement of PD-1 and the TCR/CD3 complex. This study points to mitochondria as the main targets of PD-1 inhibitory activity and shows that PD-1 engagement triggers a specific, time-dependent genetic program different from that in resting cells, suggesting that in addition to blocking TCR-mediated signals, PD-1 can target specific signaling pathways that dysregulate T cell function, including glycolysis and oxidative phosphorylation.

"Tumor-associated macrophage expression of interferon regulatory Factor-8 (IRF8) is a predictor of progression and patient survival in renal cell carcinoma," by Jason B. Muhitch et al. investigated whether levels of IRF8, a protein recently identified in nephrectomy and metastatic tissues from ccRCC patients as a regulator of myeloid-derived suppressor cells (MDSCs) and macrophage responses to pathogens, correlated with disease progression. This study evaluated IRF8 expression by TAMs and provides the first evidence that protein expression of this transcription factor is decreased in advanced stage patient specimens and may be used to predict long-term survival in a subset of ccRCC patients.

Finally, Marit M. Melssen et al.'s study, "A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund's adjuvant in melanoma patients," tested whether vaccination with 12 short melanoma peptides in combination with TLR agonists (polyICLC or LPS) with or without IFA was both safe and immunogenic in melanoma patients. In contrast to the study hypothesis, peptide-specific CD8 T cell responses were more durable and of greater magnitude when IFA was included as an adjuvant, regardless of whether it was combined with polyICLC or LPS.

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


JITC Editor Picks

Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III–IV melanoma

Robert H. I. Andtbacka, Frances Collichio, Kevin J. Harrington, Mark R. Middleton, Gerald Downey, Katarina Ohrling and Howard L. Kaufman
Journal for ImmunoTherapy of Cancer, 7:145 (6 June 2019)
Short Report

Summary:

OPTiM is the first and largest randomized phase 3 trial to demonstrate a clinical benefit with the oncolytic immunotherapy talimogene laherparepvec (T-VEC), in unresectable stage IIIB/C melanoma. T-VEC was shown to significantly improve durable response rate (DRR), objective response rate (ORR), overall survival (OS) and quality of life in patients with recurrent melanoma with unresectable, cutaneous, subcutaneous and nodal lesions when compared to treatment with subcutaneous GM-CSF. Here, Andtbacka et al. present the OPTiM final analysis for OS, objective response and complete responders 3 years later in both the overall intent-to-treat population and patients with early metastatic disease. Results of this updated study confirm a longer-term effect on OS associated with high and durable CR rates, especially in the subgroup of patients with early metastatic melanoma.

DNA damage repair gene mutations and their association with tumor immune regulatory gene expression in muscle invasive bladder cancer subtypes

Thiago Vidotto, Sarah Nersesian, Charles Graham, D. Robert Siemens and Madhuri Koti
Journal for ImmunoTherapy of Cancer, 7:148 (7 June 2019)
Research Article

Summary:

Urothelial cancers (UCs) have a high tumor mutational burden, conferring high immunogenicity; however, only a small subset of patients with metastatic UC have demonstrated durable responses with immune checkpoint blockade (ICB). Leveraging the TCGA database, Vidotto et al. investigated DNA damage response (DDR) mutations associated with the pre-treatment immune landscape for patients with muscle invasive urothelial cancer (MIUC) to guide future biomarker directed immunotherapy treatment combinations. Through correlation of expression profiles of a panel of immune regulatory genes using whole transcriptomic data, this study tests the hypothesis that pre-treatment immune contexture and subsequent response of MIUC is dictated by cancer cell intrinsic events such as DDR deficiency. Results suggest the potential co-activation of multiple compensatory immune checkpoint pathways in pre-treatment MIUC, providing rationale for use of combination ICB treatment.

PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8+ T lymphocytes

Jesús Ogando, María Eugenia Sáez, Javier Santos, Cristina Nuevo-Tapioles, Marta Gut, Anna Esteve-Codina, Simon Heath, Antonio González-Pérez, José M. Cuezva, Rosa Ana Lacalle and Santos Mañes
Journal for ImmunoTherapy of Cancer, 7:151 (13 June 2019)
Research Article

Summary:

Pre-clinical studies show that PD-1 engagement and stimulation dysregulates both glycolysis and oxidative metabolism in activated T cells; however, the mechanisms by which PD-1 affects mitochondrial function are largely unknown. Ogando et al. analyzed the gene expression profiles of human CD8+ T cells in conditions that mimic simultaneous engagement of PD-1 and the TCR/CD3 complex. Results demonstrated that PD-1 engagement triggers a specific, time-dependent genetic program different from that detected in resting cells, suggestive of the ability of PD-1 to generate specific signaling pathways which deregulate T cell function. This study points to mitochondria as the main targets of PD-1 inhibitory activity, in turn, inducing metabolic rewiring and irreversible mitochondrial dysfunction. Results presented here may begin to explain the reduction in the number and length of mitochondrial cristae in PD-1-engaged cells. Next steps will involve developing strategies to restore signaling patterns downstream of PD-1 in order to reinvigorate anti-tumor immune responses in vivo.

Tumor-associated macrophage expression of interferon regulatory Factor-8 (IRF8) is a predictor of progression and patient survival in renal cell carcinoma

Jason B. Muhitch, Nicholas C. Hoffend, Gissou Azabdaftari, Austin Miller, Wiam Bshara, Carl D. Morrison, Thomas Schwaab and Scott I. Abrams
Journal for ImmunoTherapy of Cancer, 7:155 (20 June 2019)
Short Report

Summary:

In diverse solid tumor types such as clear cell renal cell carcinoma (ccRCC), tumor-associated macrophages (TAMs) in the tumor microenvironment generally correlate with poorer outcomes, while infiltration of antitumor macrophages have been correlated with improved survival. Recent pre-clinical studies have identified interferon regulatory factor-8 (IRF8), a key transcription factor of monocyte/macrophage development and function, as a regulator of myeloid-derived suppressor cells (MDSCs) and macrophage responses to pathogens. Muhitch et al. investigated whether the level of IRF8 in nephrectomy and metastatic tissues from ccRCC patients correlated with disease progression. Results presented in this study indicate that macrophage expression of IRF8 is inversely correlated with tumor mass and survival benefit, and may be used to predict long-term survival in a subset of patients with ccRCC.

A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund's adjuvant in melanoma patients

Marit M. Melssen, Gina R. Petroni, Kimberly A. Chianese-Bullock, Nolan A. Wages, William W. Grosh, Nikole Varhegyi, Mark E. Smolkin, Kelly T. Smith, Nadejda V. Galeassi, Donna H. Deacon, Elizabeth M. Gaughan and Craig L. Slingluff Jr
Journal for ImmunoTherapy of Cancer, 7:163 (27 June 2019)
Research Article

Summary:

There is a lack of consensus regarding optimal vaccine adjuvants, with the most common adjuvant for peptide vaccines in melanoma being an incomplete Freund's adjuvant (IFA). Recent pre-clinical studies have shown negative effects of IFA, and suggest that an optimal adjuvant for short peptide vaccines may be a TLR agonist plus an agonistic CD40 antibody, which may induce strong and durable T cell responses. With the hypothesis that TLR agonists would be safe and effective vaccine adjuvants and that decreasing use of IFA may further enhance the magnitude and persistence of an immune response, Melssen et al. evaluated whether vaccinating with a mixture of 12 short melanoma peptides (12MP) plus a tetanus helper peptide, in combination with TLR agonists (polyICLC or LPS) with or without IFA, would be safe and immunogenic in melanoma patients. In contrast to initial thought, peptide-specific CD8 T cell responses were found to be more robust and durable when IFA was included as an adjuvant, regardless of combination with polyICLC or LPS.

PD-L1 detection using 89Zr-atezolizumab immuno-PET in renal cell carcinoma tumorgrafts from a patient with favorable nivolumab response

Joseph Vento, Aditi Mulgaonkar, Layton Woolford, Kien Nham, Alana Christie, Aditya Bagrodia, Alberto Diaz de Leon, Raquibul Hannan, Isaac Bowman, Renee M. McKay, Payal Kapur, Guiyang Hao, Xiankai Sun and James Brugarolas
Journal for ImmunoTherapy of Cancer, 7:144 (3 June 2019)
Case Report

Opportunities and challenges of active immunotherapy in dogs with B-cell lymphoma: a 5-year experience in two veterinary oncology centers

Laura Marconato, Luca Aresu, Damiano Stefanello, Stefano Comazzi, Valeria Martini, Roberta Ferrari, Fulvio Riondato, Nicole Rouquet, Patrick Frayssinet and Silvia Sabattini
Journal for ImmunoTherapy of Cancer, 7:146 (7 June 2019)
Research Article

Targeting of M2-like tumor-associated macrophages with a melittin-based pro-apoptotic peptide

Chanju Lee, Hyunju Jeong, Younghyeon Bae, Kyungmoon Shin, Sinwoo Kang, Hwikyung Kim, Jayoung Oh and Hyunsu Bae
Journal for ImmunoTherapy of Cancer, 7:147 (7 June 2019)
Research Article

CD45RA+CCR7 CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in peripheral blood of NSCLC patients responding to nivolumab

Andre Kunert, Edwin A. Basak, Daan P. Hurkmans, Hayri E. Balcioglu, Yarne Klaver, Mandy van Brakel, Astrid A. M. Oostvogels, Cor H. J. Lamers, Sander Bins, Stijn L. W. Koolen, Astrid A. M. van der Veldt, Stefan Sleijfer, Ron H. J. Mathijssen, Joachim G. J. V. Aerts and Reno Debets
Journal for ImmunoTherapy of Cancer, 7:149 (8 June 2019)
Research Article

Temporal changes within the (bladder) tumor microenvironment that accompany the therapeutic effects of the immunocytokine NHS-IL12

Y. Maurice Morillon II, Zhen Su, Jeffrey Schlom and John W. Greiner
Journal for ImmunoTherapy of Cancer, 7:150 (11 June 2019)
Research Article

Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling

Koen A. Marijt, Marjolein Sluijter, Laura Blijleven, Sofie H. Tolmeijer, Ferenc A. Scheeren, Sjoerd H. van der Burg and Thorbald van Hall
Journal for ImmunoTherapy of Cancer, 7:152 (13 June 2019)
Research Article

B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors

William Damsky, Lucia Jilaveanu, Noel Turner, Curtis Perry, Christopher Zito, Mary Tomayko, Jonathan Leventhal, Kevan Herold, Eric Meffre, Marcus Bosenberg and Harriet M. Kluger
Journal for ImmunoTherapy of Cancer, 7:153 (14 June 2019)
Short Report

Tumor-associated macrophage expression of interferon regulatory Factor-8 (IRF8) is a predictor of progression and patient survival in renal cell carcinoma

Jason B. Muhitch, Nicholas C. Hoffend, Gissou Azabdaftari, Austin Miller, Wiam Bshara, Carl D. Morrison, Thomas Schwaab and Scott I. Abrams
Journal for ImmunoTherapy of Cancer, 7:155 (20 June 2019)
Short Report

Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancer

Song Liu, Junko Matsuzaki, Lei Wei, Takemasa Tsuji, Sebastiano Battaglia, Qiang Hu, Eduardo Cortes, Laiping Wong, Li Yan, Mark Long, Anthony Miliotto, Nicholas W. Bateman, Shashikant B. Lele, Thinle Chodon, Richard C. Koya, Song Yao, Qianqian Zhu, Thomas P. Conrads, Jianmin Wang, George L. Maxwell, Amit A. Lugade and Kunle Odunsi
Journal for ImmunoTherapy of Cancer, 7:156 (20 June 2019)
Research Article

Type I interferon suppresses tumor growth through activating the STAT3-granzyme B pathway in tumor-infiltrating cytotoxic T lymphocytes

Chunwan Lu, John D. Klement, Mohammed L. Ibrahim, Wei Xiao, Priscilla S. Redd, Asha Nayak-Kapoor, Gang Zhou and Kebin Liu
Journal for ImmunoTherapy of Cancer, 7:157 (22 June 2019)
Research Article

Comparative safety and efficacy of anti-PD-1 monotherapy, chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: findings from recent advances in landmark trials

Jia-Wei Lv, Jun-Yan Li, Lin-Na Luo, Zi-Xian Wang and Yu-Pei Chen
Journal for ImmunoTherapy of Cancer, 7:159 (25 June 2019)
Commentary

Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: a promising new combination

Mathieu Grapin, Corentin Richard, Emeric Limagne, Romain Boidot, Véronique Morgand, Aurélie Bertaut, Valentin Derangere, Pierre-Antoine Laurent, Marion Thibaudin, Jean David Fumet, Gilles Crehange, François Ghiringhelli and Céline Mirjolet
Journal for ImmunoTherapy of Cancer, 7:160 (25 June 2019)
Research Article

Pre-clinical investigation of the synergy effect of interleukin-12 gene-electro-transfer during partially irreversible electropermeabilization against melanoma

Lise Pasquet, Elisabeth Bellard, Sophie Chabot, Bostjan Markelc, Marie-Pierre Rols, Justin Teissie and Muriel Golzio
Journal for ImmunoTherapy of Cancer, 7:161 (26 June 2019)
Research Article

Response to targeted therapy or chemotherapy following immunotherapy in patients with gastrointestinal cancers - a case series

Rayan Alsuwaigh, Joycelyn Lee, Gloria Chan, Cheng Ean Chee and Su Pin Choo
Journal for ImmunoTherapy of Cancer, 7:162 (27 June 2019)
Case Report

SITC Members Receive 60 Percent Submission Discount in 2019

*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 SITC members with a 60 percent discount on processing fees for all JITC articles accepted in 2019. To take advantage of this SITC member benefit, authors must contact JITC Managing Editor Andrea Kunz at JITCEditor@sitcancer.org or 1-414-271-2456 prior to submission to obtain a discount code and instructions.