JITC Digest February 2020


Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

Welcome to the February edition of the JITC digest. The journal continues to grow and thrive, publishing impactful research across the entire spectrum of the diverse and interdisciplinary immunotherapy field. The articles in this month's digest highlight innovative approaches to overcoming longstanding challenges in cancer immunotherapy, and will surely spark important conversations moving forward.

I'm thrilled to report that this month's digest features three papers from one of the journal's new sections, Immune cell therapies and immune cell engineering—a burgeoning area that continues to push boundaries in terms of advancing scientific understanding and improving patient outcomes.

The highlighted articles feature somewhat "outside-the-box" cell therapy strategies, two of which could have exciting implications for the treatment of solid tumors. In elegant preclinical models, Rahul Suresh et al. demonstrate robust anti-tumor activity by adoptively transferred gene-edited immature myeloid cells. In a different tactic, the feasibility of generating PD-1-deficient effector memory T cells specific for melanoma antigens was demonstrated by Lucine Marotte and colleagues.

Although cell therapies have a well-established role in the treatment of hematologic malignancies, relapse remains common. In an attempt to improve outcomes, Benjamin Derman et al. demonstrate two effective strategies to significantly reduce and delay T regulatory cell recovery after autologous stem cell transplant in a pilot study of 15 patients with multiple myeloma.

In addition to the exciting articles in the cell therapy section, be sure to read the paper by Shibin Qu et al., describing a novel approach to tumor ablation that causes the release of non-denatured neoantigens and damage-associated molecular patterns capable of potentiating the efficacy of checkpoint blockade for non-immunogenic tumors in mouse models.

Our field keeps moving at a tremendous pace! If you'd like to join in to real-time conversations about the latest research and you're active on social media, be sure to take a moment to follow the official JITC Twitter handle, @jitcancer.  

Best regards,

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

JITC Editor Picks

Regulatory T-cell depletion in the setting of autologous stem cell transplantation for multiple myeloma: pilot study

Benjamin A Derman, Yuanyuan Zha, Todd M Zimmerman, Rebecca Malloy, Andrzej Jakubowiak, Michael R Bishop MD, & Justin Kline. 
Journal for ImmunoTherapy of Cancer 2020;8:e000286 (15 January 2020)


Regulatory (Treg) T cells rapidly reconstitute after autologous stem cell transplant (ASCT), possibly driving disease progression in multiple myeloma. Reasoning that reducing and delaying the recovery of Treg cells may enhance the anti-myeloma immune response after ASCT, Benjamin Derman and colleagues performed a randomized pilot study to evaluate two methods of Treg cell depletion in multiple myeloma patients undergoing transplants. In total, 15 patients were enrolled and randomized to one of three treatment arms. One group received anti-CD25 monoclonal antibody (basiliximab) on day +1 post-transplant for in vivo Treg depletion (IVTRD). For the ex vivo Treg depletion arm (EVTRD), anti-CD25 were used to deplete Treg cells from autologous stem cell grafts prior to transplant. No depletion was performed in the control arm. In the EVTRD arm, manipulation of autologous stem cell grafts was able to achieve a 90% depletion of Treg cells—decreasing the median relative frequency of CD25+ cells from 8.3% to 0.9%. After transplant, both IVTRD and EVTRD led to significant reductions compared to the control arm in Treg cell frequency in peripheral blood samples from patients between days +7 and +90. Although clinical outcomes were not primary endpoints in this study, all five patients in the EVTRD arm achieved stringent complete response and 4 out of 5 achieved minimal residual disease negativity by multicolor flow cytometry. The findings indicate that Treg cell depletion may enhance post-transplant anti-tumor response, warranting further investigation as a possible platform for other post-tranplant immunotherapies to improve outcomes after ASCT.

Increased antitumor efficacy of PD-1-deficient melanoma-specific human lymphocytes

Lucine Marotte, Sylvain Simon, Virginie Vignard, Emilie Dupre, Malika Gantier, Jonathan Cruard, Jean-Baptiste Alberge, Melanie Hussong, Cecile Deleine, Jean-Marie Heslan , Jonathan Shaffer, Tiffany Beauvais, Joelle Gaschet, Emmanuel Scotet, Delphine Fradin, Anne Jarry, Tuan Nguyen, Nathalie Labarriere
Journal for ImmunoTherapy of Cancer 2020;8:e000311  (29 January 2020)


Despite advances in cell engineering and protocols for the isolation of antigen-specific cytotoxic T lymphocytes (CTLs), the feasibility of engineering CD8+ effector/memory T cells to boost their anti-tumor activities has yet to be demonstrated. By applying CRISPR/Cas9 genome editing technology to human melanoma-specific CTLs isolated using a procedure derived from the phase 1/2 MelSort clinical trial, Lucine Marotte et al. generated and characterized PD-1-deficient effector memory CD8+ T cells. In mouse models of PD-L1-positive melanoma, the engineered CTLs significantly delayed tumor growth compared to unedited CTLs expressing an identical T cell receptor. The functional avidities of wild type and PD-1 knockout melanoma-specific CTLs were similar as well as their in vitro cytotoxic properties. Notably the engineered CTLs lacking PD-1 produced less interferon gamma and IL-2 globally compared to wild-type control CTLs, which could potentially be attributed to significant overexpression of TIGIT in the edited cells. Transcriptomic analyses revealed significantly upregulated expression of metabolism-associated genes along with decreased expression of genes related to DNA replication and proliferation in the CTLs lacking PD-1. The study suggests that the use of gene-edited lymphocytes for adoptive cell therapy, potentially in conjunction with other approaches to modulate the tumor microenvironment, could improve the efficacy of immunotherapy for solid tumors.

Non-thermal histotripsy tumor ablation promotes abscopal immune responses that enhance cancer immunotherapy

Shibin Qu, Tejaswi Worlikar, Amy E Felsted, Anutosh Ganguly, Megan V Beems, Ryan Hubbard, Ashley L Pepple, Alicia A Kevelin, Hannah Garavaglia, Joe Dib, Mariam Toma, Hai Huang, Allan Tsung, Zhen Xu, Clifford Suhyun Cho
Journal for ImmunoTherapy of Cancer 2020;8:e000200 4 (15 January 2020)


Responsiveness to checkpoint inhibitors correlates with tumor immunogenicity. Despite ongoing efforts to use tumor-directed therapies such as thermal ablation and radiation to incite inflammation within the tumor microenvironment, these strategies have not consistently proven to augment the effectiveness of immunotherapy. Hypothesizing that the protein-denaturing effects of heat and ionizing radiation limits the immunogenicity of tumor-directed therapies, Shibin Qu et al. investigated the immunostimulatory effects of histotripsy, a non-invasive tumor ablation method that disrupts cellular architecture without heat generation through high-pressure overlapping ultrasound pulses. In mouse models of non-immunogenic melanoma, histotripsy resulted in significant increases in intratumoral CD8+ T cell infiltration in the primary tumor compared to other modalities of tumor-directed therapy. The ablation method also induced a potent abscopal effect, as significant numbers of CD8+ T cells infiltrated distant tumors after contralateral histotripsy—a response not observed after radiation therapy or radiofrequency ablation. The abscopal effect of unilateral histotripsy was associated with a significant survival advantage in mice bearing bilateral tumors. The addition of histotripsy to checkpoint inhibition led to significant increases in CD8+ T cell infiltration along with delays in tumor growth compared to untreated controls or either single treatment in mouse models of melanoma as well as a poorly immunogenic hepatocellular carcinoma. The observations indicate that histotripsy stimulates local and systemic anti-tumor immune responses that may potentiate the therapeutic efficacy of checkpoint inhibition.

NF-kappa B p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma

Rahul Suresh, David J Barakat, Theresa Barberi, Lei Zheng, Elizabeth Jaffee, Kenneth J Pienta, Alan D Friedman
Journal for ImmunoTherapy of Cancer 2020;8:e000244 (13 January 2020)


Adoptive transfer of activated macrophages has been evaluated in cancer patients, but minimal anti-tumor efficacy has been observed. Based on observations that the transcription factor nuclear factor kappa B p50 promotes an anti-inflammatory, suppressive M2 phenotype in macrophages, characterized by reduced cytokine production and decreased T cell activation, Rahul Suresh and colleagues performed adoptive transfer of immature myeloid cells lacking p50 in mouse models of prostate and pancreatic ductal carcinoma. After expanding lineage-depleted bone marrow mononuclear cells from p50-/- mice, cultures were exposed to M-CSF-containing media for one day to generate immature myeloid cells (IMCs). In mice inoculated with HI-Myc prostate cancer, adoptive transfer of p50-/- IMC slowed tumor growth by 3-fold compared to treatment with wild-type IMC—though effects were only observed after pre-infusion conditioning with 5-fluorouracil (5-FU). In models of pancreatic ductal carcinoma, 5-FU treatment followed by p50-/- IMC slowed tumor growth in 50% of treated mice. Strikingly higher proportions of cells expressing dendritic cell markers were isolated from prostate carcinoma tumors after 5-FU treatment and adoptive transfer of p50-/- IMC compared to wild type IMC. Infusion of p50-/- IMC also increased the proportion of intratumoral CD8+ T cells by 5 fold compared to wild type IMC, and anti-tumor effects were significantly reduced by depletion of CD8+ cells. The results offer rationale for investigating the production of p50-deleted IMC from patient-derived marrow as a potential adoptive cell therapy.  

Histone deacetylase inhibitors valproic acid and vorinostat enhance trastuzumab-mediated antibody-dependent cell-mediated phagocytosis

Johannes Laengle, Julijan Kabiljo, Leah Hunter, Jakob Homola, Sophie Prodinger, Gerda Egger, Michael Bergmann
Journal for ImmunoTherapy of Cancer 2020;8:e000195 (2 January 2020)

Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity

João Manuel Santos, Camilla Heiniö, Victor Cervera-Carrascon, Dafne C A Quixabeira, Mikko Siurala, Riikka Havunen, Ralf Butzow, Sadia Zafar, Tanja de Gruijl, Heini Lassus, Anna Kanerva, Akseli Hemminki
Journal for ImmunoTherapy of Cancer 2020;8:e000188  (13 January 2020)

Defining current gaps in quality measures for cancer immunotherapy: consensus report from the Society for Immunotherapy of Cancer (SITC) 2019 Quality Summit

Sara Pai, David Blaisdell, Rachel Brodie, Robert Carlson, Heidi Finnes, Michele Galioto, Roxanne E Jensen, Tom Valuck, Antonia R Sepulveda, Howard L Kaufman
Journal for ImmunoTherapy of Cancer 2020;8:e000112 (16 January 2020)
Position Article and Guidelines

Correlation of plasma exosomal microRNAs with the efficacy of immunotherapy in EGFR / ALK wild-type advanced non-small cell lung cancer

Xiao-Xiao Peng, Ruo-Ying Yu, Xue Wu, Shu-Yu Wu, Can Pi, Zhi-Hong Chen, Xu-Chao Zhang, Cun-Yi Gao, Yang W Shao, Li Liu, Yi-Long Wu, Qing Zhou
Journal for ImmunoTherapy of Cancer 2020;8:e000376  (19 January 2020)

Enhanced efficacy and limited systemic cytokine exposure with membrane-anchored interleukin-12 T-cell therapy in murine tumor models

Ling Zhang, John S Davies, Carylinda Serna, Zhiya Yu, Nicholas P Restifo, Steven A Rosenberg, Richard A Morgan, Christian S Hinrichs
Journal for ImmunoTherapy of Cancer 2020;8:e000210  (19 January 2020)

HHLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma

Qiang-Hua Zhou, Kai-Wen Li, Xu Chen, Hai-Xia He, Sheng-Meng Peng, Shi-Rong Peng, Qiong Wang, Ze-An Li, Yi-Ran Tao, Wen-Li Cai, Ran-Yi Liu, Hai Huang
Journal for ImmunoTherapy of Cancer 2020;8:e000157 (19 January 2020)

Late cardiac adverse events in patients with cancer treated with immune checkpoint inhibitors

Charles Dolladille, Stephane Ederhy, Stéphane Allouche, Querntin Dupas, Radj Gervais, Jeannick Madelaine, Marion Sassier, Anne-Flore Plane, Francois Comoz, Ariel Aron Cohen, Franck Roland Thuny, Jennifer Cautela, Joachim Alexandre
Journal for ImmunoTherapy of Cancer 2020;8:e000261  (26 January 2020)

Response and outcomes after anti-CTLA4 versus anti-PD1 combined with stereotactic body radiation therapy for metastatic non-small cell lung cancer: retrospective analysis of two single-institution prospective trials

Dawei Chen, Hari Menon, Vivek Verma, Chunxiao Guo, Rishab Ramapriyan, Hampartsoum Barsoumian, Ahmed Younes, Yun Hu, Mark Wasley, Maria Angelica Cortez, James Welsh
Journal for ImmunoTherapy of Cancer 2020;8:e000492  (28 January 2020)
Short Report

SITC Members Receive 50 Percent Submission Discount in 2020

*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 2020.