JITC Digest April 2019

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Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

In the April edition of the JITC Digest, let me call your attention to the following five articles of special significance. First, “Anti-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by anti-TGF-beta antibody to promote durable rejection and immunity in squamous cell carcinomas,” by E. Dodagatta-Marri et al. details the development and characterization of a novel panel of murine syngeneic SCC lines created to reflect the heterogeneity of human lung cancer and its responses to anti-PD-1 and anti-TGF-beta therapies. This study demonstrates that anti-PD-1 not only initiates a tumor rejection program, but can also induce a competing TGF-beta-driven immuno-regulatory program in SCCs, effects that were cooperatively blocked by combined PD-1 and TGF-beta inhibition.

Next, “Collagen density regulates the activity of tumor-infiltrating T cells,” by Dorota E. Kuczek et al. reports the use of 3D culture assays to investigate the role of collagen density as a direct regulator of anti-cancer T cell activity. Such results identify a new immune modulatory mechanism dampening T cell activity in the tumor microenvironment, which could constitute a novel therapeutic target for enhancing immunotherapy efficacy.

Furthermore, the article, “Merger of dynamic two-photon and phosphorescence lifetime microscopy reveals dependence of lymphocyte motility on oxygen in solid and hematological tumors,” by Mateusz Rytelewski et al. presents a novel imaging approach developed to elucidate the effect of oxygen tension on the efficacy of anti-tumor immune therapies. Data presented here analyzes the relationship between lymphocyte motility and oxygen distribution using ‘Fast’ Scanning Two-photon Phosphorescence Lifetime Imaging Microscopy (FaST-PLIM), a bi-modal imaging regimen that merges high-resolution oxygen imaging with fluorescence-based cellular tracking in in vivo models.

“Mechanisms involved in IL-15 superagonist enhancement of anti-PD-L1 therapy,” by Karin M. Knudson et al. describes for the first time the anti-tumor efficacy of subcutaneously administered IL-15 superagonist N-803 in combination with anti-PD-L1 checkpoint blockade in murine triple negative breast and colon carcinoma models which are non- and/or minimally responsive to either monotherapy. This study provides rationale for further assessment of the clinical potential of combining N-803 with blockade of the PD-1/PD-L1 axis.

Finally, Anne Monette et al.’s article, “Immune-enrichment of non-small cell lung cancer baseline biopsies for multiplex profiling define prognostic immune checkpoint combinations for patient stratification,” propose a novel, tumor heterogeneity reducing procedure to extract information from small tumor biopsies for companion diagnostic (CDx) tests for immunotherapy of lung cancer. Developed from immune-dense regions of core needle biopsies from a baseline NSCLC cohort, this new CDx is shown to profile infiltrating immune cell subsets, ICPs, proliferation, and effector T cell markers to better stratify patients for checkpoint blockade combinations using baseline biospecimens of all sizes.

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


JITC Editor Picks

Anti-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by anti-TGF-beta antibody to promote durable rejection and immunity in squamous cell carcinomas

E. Dodagatta-Marri, D. S. Meyer, M. Q. Reeves, R. Paniagua, M. D. To, M. Binnewies, M. L. Broz, H. Mori, D. Wu, M. Adoumie, R. Del Rosario, O. Li, T. Buchmann, B. Liang, J. Malato, F. Arce Vargus, D. Sheppard, B. C. Hann, A. Mirza, S. A. Quezada, M. D. Rosenblum, M. F. Krummel, A. Balmain and R. J. Akhurst
Journal for ImmunoTherapy of Cancer, 7:62 (4 March 2019)
Research Article

Summary:

Immune checkpoint inhibitor (ICI) therapy has moved into the first- and second-line therapy regimens for numerous cancers. Paradoxically, anti-PD-1 therapy has also been shown to accelerate tumor growth in certain patients by unknown mechanisms. Given the correlation between clinical response to ICI therapy and tumor mutational load, the present study by Dodagatta-Marri et al. systemically analyzed the effects of anti-PD-1 and anti-TGF-beta therapy in cutaneous squamous cell carcinomas (cSCC) cell lines derived from chemically induced carcinomas with a high mutation burden, similar to that of environmentally-induced human cancers. Results demonstrate that while anti-PD-1 can initiate both a tumor rejection program and a competing TGF-beta-driven immuno-suppressive program in SCCs, these effects were effectively thwarted by combined PD-1 and TGF-beta inhibition.

Collagen density regulates the activity of tumor-infiltrating T cells

Dorota E. Kuczek, Anne Mette H. Larsen, Marie-Louise Thorseth, Marco Carretta, Adrija Kalvisa, Majken S. Siersbæk, Ana Micaela C. Simões, Anne Roslind, Lars H. Engelholm, Elfriede Noessner, Marco Donia, Inge Marie Svane, Per thor Straten, Lars Grøntved and Daniel H. Madsen
Journal for ImmunoTherapy of Cancer, 7:68 (12 March 2019)
Research Article

Summary:

The tumor microenvironment consists of non-malignant stromal cells and immune cells as well the extracellular matrix (ECM). While the ECM is known to augment many cancer processes, such as angiogenesis and the activation of invasion and metastasis, its ability to modulate the immunosuppressive tumor microenvironment is not fully understood. To better appreciate the role of the EMC in tumor immune evasion, Kuczek et al. employed 3D culture assays to assess the role of collagen density as a regulator of anti-cancer T cell activity. The immunosuppressive mechanism uncovered in this study appears to play a key role in the cancer cells’ evasion of immune-destruction and is suggestive of a novel therapeutic target for enhancing immunotherapy efficacy.

Merger of dynamic two-photon and phosphorescence lifetime microscopy reveals dependence of lymphocyte motility on oxygen in solid and hematological tumors

Mateusz Rytelewski, Karine Haryutyunan, Felix Nwajei, Meenakshi Shanmugasundaram, Patrick Wspanialy, M. Anna Zal, Chao-Hsien Chen, Mirna El Khatib, Shane Plunkett, Sergei A. Vinogradov, Marina Konopleva and Tomasz Zal
Journal for ImmunoTherapy of Cancer, 7:78 (18 March 2019)
Research Article

Summary:

In many tumors, infiltrating lymphocytes (TILs) come across a hostile microenvironment that is often depleted of oxygen. This relationship between oxygen availability and TILs anti-tumor function remains unclear due in part to a general difficulty in the microscopic imaging of living tissue oxygenation with simultaneous visualization of cell dynamics. To address this disconnect, Rytelewski et al. have devised an imaging array combining intravital oxygen and cell dynamics co-imaging, termed ‘Fast’ Scanning Two-photon Phosphorescence Lifetime Imaging Microscopy (FaST-PLIM). This technology enables direct visualization of the cellular motility of T-lymphocytes in relation to the microscopic distribution of oxygen, thus providing the ability to map tissue oxygen in vivo at cellular resolution.

Mechanisms involved in IL-15 superagonist enhancement of anti-PD-L1 therapy

Karin M. Knudson, Kristin C. Hicks, Sarah Alter, Jeffrey Schlom and Sofia R. Gameiro
Journal for ImmunoTherapy of Cancer, 7:82 (21 March 2019)
Research Article

Summary:

An IL-15 superagonist, N-803 enhances IL-15 biological activity and stability in vivo and promotes greater activation of CD8+ T cells and NK cells than recombinant IL-15, with less toxicity. However, perhaps due to immune suppression in the tumor microenvironment, N-803 monotherapy was not curative in most murine solid carcinoma studies. Following the results of a study by Kinter et al. demonstrating that recombinant IL-15 induces PD-L1 expression in vitro on immune cells, Knudson et al. provides novel data demonstrating the anti-tumor efficacy of subcutaneous administration of N-803 in combination with PD-L1 inhibition in multiple murine solid carcinoma models. This study reports the immune-mediated mechanism of action of N-803 plus anti-PD-L1, providing rationale for further clinical assessment of N-803 plus PD-1/PD-L1 blockade combination therapy.

Immune-enrichment of non-small cell lung cancer baseline biopsies for multiplex profiling define prognostic immune checkpoint combinations for patient stratification

Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Anne-Marie Mes-Masson, Nidhameddine Kchir, Kamel Hamzaoui, Igor Jurisica and Réjean Lapointe
Journal for ImmunoTherapy of Cancer, 7:86 (28 March 2019)
Research Article

Summary:

Monette et al. address the critical need for the development of biopsy-adaptable companion diagnostic (CDx) tests. The authors propose the construction of tissue microarrays composed of selected regions of small baseline lung tumor biopsies enriched for immune cell infiltrates. Their proposal is to recur to this approach as a way to circumvent tissue heterogeneity and profile immune checkpoint (ICP) co-expression dynamics as well as ICP linkage to clinical parameters and infiltrating immune cell subsets. With the goal of defining the most prognostic combinations for ICP therapies, this study reports that ICP expression on NSCLC TILs was positively associated with survival and identifies BTLA as the most reproducible prognostic biomarker spanning all cohorts investigated.

Exceptional response and multisystem autoimmune-like toxicities associated with the same T cell clone in a patient with uveal melanoma treated with immune checkpoint inhibitors

Suthee Rapisuwon, Benjamin Izar, Cory Batenchuk, Alexandre Avila, Shaolin Mei, Peter Sorger, Jerry M. Parks, Sarah J. Cooper, David Wagner, Jay C. Zeck, Aline J. Charabaty and Michael B. Atkins
Journal for ImmunoTherapy of Cancer, 7:61 (4 March 2019)
Case Report

Radiotherapy enhances responses of lung cancer to CTLA-4 blockade

Anna Wilkins, Fiona McDonald, Kevin Harrington and Alan Melcher
Journal for ImmunoTherapy of Cancer, 7:64 (6 March 2019)
Commentary

Expression and clinical significance of PD-L1, B7-H3, B7-H4 and TILs in human small cell lung Cancer (SCLC)

Daniel Carvajal-Hausdorf, Mehmet Altan, Vamsidhar Velcheti, Scott N. Gettinger, Roy S. Herbst, David L. Rimm and Kurt A. Schalper
Journal for ImmunoTherapy of Cancer, 7:65 (8 March 2019)
Research Article

Complete response of renal cell carcinoma vena cava tumor thrombus to neoadjuvant immunotherapy

Craig Labbate, Ken Hatogai, Ryan Werntz, Walter M. Stadler, Gary D. Steinberg, Scott Eggener and Randy F. Sweis
Journal for ImmunoTherapy of Cancer, 7:66 (11 March 2019)
Case Report

Antisense oligonucleotide targeting CD39 improves anti-tumor T cell immunity

Abhishek S. Kashyap, Tamara Thelemann, Richard Klar, Sandra M. Kallert, Julia Festag, Melanie Buchi, Lisa Hinterwimmer, Monika Schell, Sven Michel, Frank Jaschinski and Alfred Zippelius
Journal for ImmunoTherapy of Cancer, 7:67 (12 March 2019)
Research Article

Evaluating in vivo efficacy – toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells

Inez Johanna, Trudy Straetemans, Sabine Heijhuurs, Tineke Aarts-Riemens, Håkan Norell, Laura Bongiovanni, Alain de Bruin, Zsolt Sebestyen and Jürgen Kuball
Journal for ImmunoTherapy of Cancer, 7:69 (12 March 2019)
Research Article

Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab

Amy K. Erbe, Wei Wang, Lakeesha Carmichael, Anna Hoefges, Bartosz Grzywacz, Patrick K. Reville, Erik A. Ranheim, Jacquelyn A. Hank, KyungMann Kim, Songwon Seo, Eneida A. Mendonca, Yiqiang Song, Vaishalee P. Kenkre, Fangxin Hong, Randy D. Gascoyne, Elisabeth Paietta, Sandra J. Horning, Jeffrey S. Miller, Brad Kahl and Paul M. Sondel
Journal for ImmunoTherapy of Cancer, 7:70 (12 March 2019)
Research Article

Perception of cure among patients with metastatic genitourinary cancer initiating immunotherapy

Cristiane Decat Bergerot, Paulo Gustavo Bergerot, Errol J. Philip, Jo Ann Hsu, Nazli Dizman, Ulka Vaishampayan, Tanya Dorff and Sumanta Kumar Pal
Journal for ImmunoTherapy of Cancer, 7:71 (12 March 2019)
Short Report

An interim report on the investigator-initiated phase 2 study of pembrolizumab immunological response evaluation (INSPIRE)

Derek L. Clouthier, Scott C. Lien, S. Y. Cindy Yang, Linh T. Nguyen, Venkata S. K. Manem, Diana Gray, Michael Ryczko, Albiruni R. A. Razak, Jeremy Lewin, Stephanie Lheureux, Ilaria Colombo, Philippe L. Bedard, David Cescon, Anna Spreafico, Marcus O. Butler, Aaron R. Hansen, Raymond W. Jang, Sangeet Ghai, Ilan Weinreb, Valentin Sotov, Ramy Gadalla, Babak Noamani, Mengdi Guo, Sawako Elston, Amanda Giesler, Sevan Hakgor, Haiyan Jiang, Tracy McGaha, David G. Brooks, Benjamin Haibe-Kains, Trevor J. Pugh, Pamela S. Ohashi and Lillian L. Siu
Journal for ImmunoTherapy of Cancer, 7:72 (13 March 2019)
Research Article

Cocultures of human colorectal tumor spheroids with immune cells reveal the therapeutic potential of MICA/B and NKG2A targeting for cancer treatment

Tristan Courau, Julie Bonnereau, Justine Chicoteau, Hugo Bottois, Romain Remark, Laura Assante Miranda, Antoine Toubert, Mathieu Blery, Thomas Aparicio, Matthieu Allez and Lionel Le Bourhis
Journal for ImmunoTherapy of Cancer, 7:74 (14 March 2019)
Research Article

Therapeutic efficacy, pharmacokinetic profiles, and toxicological activities of humanized antibody-drug conjugate Zt/g4-MMAE targeting RON receptor tyrosine kinase for cancer therapy

Hang-Ping Yao, Liang Feng, Sreedhar Reddy Suthe, Ling-Hui Chen, Tian-Hao Weng, Chen-Yu Hu, Eun Sung Jun, Zhi-Gang Wu, Wei-Lin Wang, Song Cheol Kim, Xiang-Min Tong and Ming-Hai Wang
Journal for ImmunoTherapy of Cancer, 7:75 (14 March 2019)
Research Article

HHLA2 in intrahepatic cholangiocarcinoma: an immune checkpoint with prognostic significance and wider expression compared with PD-L1

Chu-Yu Jing, Yi-Peng Fu, Yong Yi, Mei-Xia Zhang, Su-Su Zheng, Jin-Long Huang, Wei Gan, Xin Xu, Jia-Jia Lin, Juan Zhang, Shuang-Jian Qiu and Bo-Heng Zhang
Journal for ImmunoTherapy of Cancer, 7:77 (18 March 2019)
Research Article

Interleukin-1 alpha increases anti-tumor efficacy of cetuximab in head and neck squamous cell carcinoma

Madelyn Espinosa-Cotton, Samuel N. Rodman III, Kathleen A. Ross, Isaac J. Jensen, Kenley Sangodeyi-Miller, Ayana J. McLaren, Rachel A. Dahl, Katherine N. Gibson-Corley, Adam T. Koch, Yang-Xin Fu, Vladimir P. Badovinac, Douglas Laux, Balaji Narasimhan and Andrean L. Simons
Journal for ImmunoTherapy of Cancer, 7:79 (19 March 2019)
Research Article

Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma

Geoffrey T. Gibney, Omid Hamid, Jose Lutzky, Anthony J. Olszanski, Tara C. Mitchell, Thomas F. Gajewski, Bartosz Chmielowski, Brent A. Hanks, Yufan Zhao, Robert C. Newton, Janet Maleski, Lance Leopold and Jeffrey S. Weber
Journal for ImmunoTherapy of Cancer, 7:80 (20 March 2019)
Research Article

A phase II clinical trial of adoptive transfer of haploidentical natural killer cells for consolidation therapy of pediatric acute myeloid leukemia

Rosa Nguyen, Huiyun Wu, Stanley Pounds, Hiroto Inaba, Raul C. Ribeiro, David Cullins, Barbara Rooney, Teresa Bell, Norman J. Lacayo, Kenneth Heym, Barbara Degar, Deborah Schiff, William E. Janssen, Brandon Triplett, Ching-Hon Pui, Wing Leung and Jeffrey E. Rubnitz
Journal for ImmunoTherapy of Cancer, 7:81 (20 March 2019)
Short Report

Checkpoint inhibition immunotherapy for advanced local and systemic conjunctival melanoma: a clinical case series

Paul T. Finger and Anna C. Pavlick
Journal for ImmunoTherapy of Cancer, 7:83 (25 March 2019)
Short Report

Overall survival by clinical risk category for high dose interleukin-2 (HD IL-2) treated patients with metastatic renal cell cancer (mRCC): data from the PROCLAIMSM registry

M. Fishman, J. P. Dutcher, J. I. Clark, A. Alva, G. P. Miletello, B. Curti, Neeraj Agarwal, R. Hauke, K. M. Mahoney, H. Moon, J. Treisman, S. S. Tykodi, G. Daniels, M. A. Morse, M. K. K. Wong, H. Kaufman, N. Gregory and D. F. McDermott
Journal for ImmunoTherapy of Cancer, 7:84 (27 March 2019)
Research Article

Lymphopenia in Cancer Patients and its Effects on Response to Immunotherapy: an opportunity for combination with Cytokines?

Christine Ménétrier-Caux, Isabelle Ray-Coquard, Jean-Yves Blay and Christophe Caux
Journal for ImmunoTherapy of Cancer, 7:85 (28 March 2019)
Review

Use of targeted next generation sequencing to characterize tumor mutational burden and efficacy of immune checkpoint inhibition in small cell lung cancer

Biagio Ricciuti, Sasha Kravets, Suzanne E. Dahlberg, Renato Umeton, Adem Albayrak, Safiya J. Subegdjo, Bruce E. Johnson, Mizuki Nishino, Lynette M. Sholl and Mark M. Awad
Journal for ImmunoTherapy of Cancer, 7:87 (28 March 2019)
Research Article

Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition

Girish S. Naik, Sushrut S. Waikar, Alistair E. W. Johnson, Elizabeth I. Buchbinder, Rizwan Haq, F. Stephen Hodi, Jonathan D. Schoenfeld and Patrick A. Ott
Journal for ImmunoTherapy of Cancer, 7:89 (28 March 2019)
Research Article

Interaction of host immunity with HER2-targeted treatment and tumor heterogeneity in HER2-positive breast cancer

Gaia Griguolo, Tomás Pascual, Maria Vittoria Dieci, Valentina Guarneri and Aleix Prat
Journal for ImmunoTherapy of Cancer, 7:90 (29 March 2019)
Review

Proteomic test for anti-PD-1 checkpoint blockade treatment of metastatic melanoma with and without BRAF mutations

Paolo A. Ascierto, Mariaelena Capone, Antonio M. Grimaldi, Domenico Mallardo, Ester Simeone, Gabriele Madonna, Heinrich Roder, Krista Meyer, Senait Asmellash, Carlos Oliveira, Joanna Roder and Julia Grigorieva
Journal for ImmunoTherapy of Cancer, 7:91 (29 March 2019)
Short 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.