JITC Digest November 2021


Inside this Issue:

Letter from the Editor

Hello JITC Readers,pedro-romero_1__1_.jpg

I want to begin this edition of the JITC digest by thanking everybody who stopped by the meet-the-editor session at the booth at SITC’s 36th Annual Meeting and Pre-Conference Programs—it was wonderful to see JITC readers in vivo and discuss cutting-edge science in person.

One of the highlights of the meeting was presenting awards to the authors of the best papers published in JITC over the past year. You can find links to the award-winning papers across categories in this month’s special feature. Of course, selecting just one paper from each category for the prize was a difficult task given the exceptional quality of research in the journal, so be sure to browse some of the popular papers from the archives for further reading.

I also want to extend a heartfelt congratulations to James L. Gulley, MD, PhD, FACP on receiving the 2021 Pedro J. Romero Service to JITC Award. James is not only an outstanding clinician-scientist, but also an insightful and generous colleague whose vision has been invaluable in making JITC the top-tier journal it is today.

Also central to JITC’s continued upward trajectory are the high-quality papers published each month, and the highlights in this edition are no exception.

Microsatellite stable colorectal and pancreatic cancers have historically been unamenable to immunotherapy approaches, yet Meggy Suarez-Carmona and colleagues report promising results from a phase I/II trial evaluating pembrolizumab plus antagonism of CXCL12 for these challenging tumors.

The groundwork for a universal donor platform for adoptive cell therapies is set by Marie Tourret et al who demonstrate that the mucosal-associated invariant T (MAIT) cells that recognize microbial riboflavin-derived antigens have virtually zero alloreactive potential.

Compelling data to inform sequencing decisions for first-line ipilimumab plus nivolumab over BRAF/MEK inhibition for the treatment of BRAF-mutant melanoma brain metastases is provided by Peter Kar Han Lau and colleagues who find very low response rates with combination immunotherapy and evidence for resistance to anti-PD-1 in tumors treated with dabrafenib plus trametinib.

Finally, Carla S Walti et al find evidence for immunogenicity of seasonal flu vaccines in CAR T cell therapy recipients, although a relatively weak humoral response suggests additional infection-prevention strategies are needed for this vulnerable population.

Thank you, JITC readers for your continued support of the journal, and if we were not able to connect in person at SITC 2021 then I hope we can look forward to the next meeting in 2022.


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

JITC Editor Picks

Combined inhibition of CXCL12 and PD-1 in MSS colorectal and pancreatic cancer: modulation of the microenvironment and clinical effects

Meggy Suarez-Carmona, Anja Williams, Jutta Schreiber, Nicolas Hohmann, Ulrike Pruefer, Jürgen Krauss, Dirk Jäger, Anna Frömming, Diana Beyer, Dirk Eulberg, Jarf Ulf Jungelius, Matthias Baumann, Aram Mangasarian, Niels Halama

Journal for ImmunoTherapy of Cancer 2021;9:e002505 (4 October 2021)


Inhibition of the chemokine CXCL12 has been demonstrated to alleviate T cell exclusion from the tumor microenvironment (TME) in preclinical models, but clinical experience with the strategy is largely limited to hematologic malignancies. Meggy Suarez-Carmona and colleagues report disease control and TME modulation with anti-CXCL12 in combination with pembrolizumab in patients with advanced stage, heavily pretreated metastatic colorectal and pancreatic cancer in the phase I/II OPERA trial (KEYNOTE-559, NCT03168139). A total of 20 patients with microsatellite stable metastatic colorectal (n = 11) or pancreatic cancer (n = 9) were enrolled and treated with twice weekly fixed dose olaptesed pegol (an anti-CXCL12 L-RNA aptamer also called NOX-A12) monotherapy for 2 weeks followed by combination therapy with 200 mg pembrolizumab every 3 weeks until disease progression or limiting toxicity. Paired needle biopsies from liver metastases were collected pre- and post-monotherapy with NOX-A12. Treatment was safe and well-tolerated. The most common adverse events were abdominal pain, fatigue and peripheral edema, and no new safety signals emerged. Although no objective responses by RECIST v1.1 were observed, 7 out of 20 patients remained on study treatment for more than 6 months and a disease control rate of 25% was observed. Lower numbers of infiltrating T cells at baseline compared to expected values in the literature were seen in the heavily pre-treated patients in the OPERA trial. Multiplex quantification of 50 cytokines, chemokines, and growth factors revealed three distinct clusters of tissue response, categorizable by the degree of IL-2, interferon-gamma and IL-16 signature versus decrease in Th1 cytokines and IL-16 and CXCL10. A unique population of CD14+CD15+ promonocytic precursor cells were identified that localized with CXCL12. The findings support future studies of the combinatorial strategy focusing on one tumor entity and including patients with fewer prior lines of treatment.

Human MAIT cells are devoid of alloreactive potential: prompting their use as universal cells for adoptive immune therapy

Marie Tourret, Nana Talvard-Balland, Marion Lambert, Ghada Ben Youssef, Mathieu F Chevalier, Armelle Bohineust, Thomas Yvorra, Florence Morin, Saba Azarnoush, Olivier Lantz, Jean-Hugues Dalle, Sophie Caillat-Zucman

Journal for ImmunoTherapy of Cancer 2021;9:e003123  (6 October 2021)



Recent transcriptomic studies have identified new tissue repair and regulatory functions for the liver- and barrier tissue-localized mucosal-associated invariant T (MAIT) cells that recognize microbial riboflavin-derived antigens. To explore the potential for MAIT cells as adoptive therapies, Marie Tourret and colleagues profiled population dynamics and alloreactivity of MAIT cells in a variety of in vitro and in vivo models, including human patients post-stem cell transplant. Longitudinal peripheral blood mononuclear cells (PBMCs) samples collected from two cohorts of children and one cohort of adults who underwent allogeneic hematopoietic stem cell transplantation (HSCT) revealed gradually recovering numbers of T cells starting 1 month after transplantation and returning almost to normal levels by the 1 year mark with practically zero increase in the number of MAIT cells. Even 2 years HSCT, MAIT cell values remained five times lower than in age-matched donors. The reconstitution of MAIT cells and T cells were both impaired in patients that experienced severe acute graft versus host disease (GVHD). In vitro, MAIT cells proliferated in response to IL-15 and IL-17 but not IL-2, with higher numbers of replications when microbial metabolites were present in the culture medium. In the absence of the microbial metabolite, MAIT cells barely proliferated in response to stimulation by allogeneic cells. In murine models of xenogenic GVHD where MAIT cells were co-injected along with human PBMCs, virtually no proliferation of the MAIT cells occurred. Even when mice were co-injected with microbial metabolites or recombinant human IL-15 leading to massive expansion and infiltration of xenogenic T cells, MAIT cells were barely detectable. The findings set the stage for exploration of MAIT cells as universal donor platforms for adoptive cell therapies.

Melanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES)

Peter Kar Han Lau, Breon Feran, Lorey Smith, Arian Lasocki, Ramyar Molania, Kortnye Smith, Alison Weppler, Christopher Angel, Damien Kee, Prachi Bhave, Belinda Lee, Richard J Young, Amir Iravani, Hanxian Aw Yeang, Ismael A Vergara, David Kok, Kate Drummond, Paul Joseph Neeson, Karen E Sheppard, Tony Papenfuss, Benjamin J Solomon, Shahneen Sandhu, Grant A McArthur
Journal for ImmunoTherapy of Cancer
2021;9:e002995 (8 October 2021)


First-line treatment with either dabrafenib plus trametinib or ipilimumab plus nivolumab is associated with intracranial response rates of roughly 50% for melanoma brain metastases, however, resistance to BRAF/MEK inhibition emerges rapidly and the impact of sequencing on efficacy of subsequent lines of therapy is not known. Peter Kar Han Lau and colleagues provide evidence that the activity of ipilimumab plus nivolumab after prior treatment with dabrafenib plus trametinib is very poor and further show that tumors that progress on BRAF/MEK inhibition exhibit gene expression profiles characteristic of resistance to anti-PD-1. At the time of the study, reimbursement requirements in Australia mandated that treatment with BRAF/MEK inhibition in the first line for BRAFV600-mutant melanoma, so the majority of patients receiving upfront ipilimumab plus nivolumab had BRAF wild-type disease. For the 25 patients in the single-center cohort who received ipilimumab plus nivolumab in the first line, the response rate was 75% compared with a response rate of only 4.8% among the 30 patients that were treated with combination immunotherapy in the second or third line after BRAF/MEK inhibition. In cases where extracranial responses could be assessed by FDG-PET, the rates were generally in line with the intracranial responses at 82.4% (14/17) and 11.1% (1/9) for first line and second/third line ipilimumab–nivolumab, respectively. RNA sequencing analysis of 18 systemic therapy-naïve tumor samples and 14 samples from tumor that progressed after BRAF/MEK inhibition derived from 29 patients revealed differential expression of genes encoding a range of structural, signaling, metabolic, and myeloid activation cellular functions as well as upregulation of monocyte and myeloid chemokines associated with tumor-associated macrophages and monocyte derived myeloid-derived suppressor cells. Also enriched in the post-progression samples was the 26 gene pathway Innate Anti-PD1 Resistance Signature (IPRES). The study offers mechanistic and clinical evidence to inform choice of immunotherapy over targeted therapy for frontline treatment of melanoma brain metastases.

Humoral immunogenicity of the seasonal influenza vaccine before and after CAR-T-cell therapy: a prospective observational study

Carla S Walti, Andrea N Loes, Kiel Shuey, Elizabeth M Krantz, Jim Boonyaratanakornkit, Jacob Keane-Candib, Tillie Loeffelholz, Caitlin R Wolf, Justin J Taylor, Rebecca A Gardner, Damian J Green, Andrew J Cowan, David G Maloney, Cameron J Turtle, Steven A Pergam, Helen Y Chu, Jesse D Bloom, Joshua A Hill

Journal for ImmunoTherapy of Cancer 2021;9:e003428 (26 October 2021)



Respiratory tract infections are among the most common complications after CAR T cell therapy and extremely sparse data are available on the relative efficacy and immunogenicity of vaccines to common circulating pathogens after B cell-depleting adoptive cell therapies. Carla S Walti and colleagues prospectively enrolled for observation and evaluation of antibody titers and responses a total of 18 patients undergoing treatment with CD19-, CD20-, and BCMA-directed CAR T cell therapy and eight healthy adult controls, all of whom were planning to receive the four-strain inactivated vaccine for seasonal flu. Among the five patients who received the vaccine prior to undergoing CAR T cell therapy 40% (n = 2; 95% CI 12% to 77%) had antibody responses to at least one vaccine strain. Antibody titers decreased after CAR T cell therapy infusion, but neutralizing titers to one strain remained above baseline for at least 30 days. For the 13 patients who received the flu vaccine after CAR T cell treatment, responses to at least one vaccine strain were seen in 31% of the cohort (n = 4; 95% CI 13% to 58%). Responses to at least one vaccine strain were seen at a similar rate in the healthy control participants, at a rate of 38% (n = 3). Most of the participants that did have a response to the vaccine had IgA and IgM levels below the lower limit of normal and univariate logistic regression analyses in the cohort that was vaccinated after CAR T cell treatment did not identify any associations between an antibody response and age, sex, underlying malignancy, time from CAR T cell therapy, IgG level, CD19+ B cell count, or CD4+ T cell count. The findings are one of the first reports of vaccine immunogenicity after CAR T cell therapy and support consideration for vaccination for influenza and other pathogens in patients undergoing treatment.

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JITC Award Recipients at SITC 2021

2021 Pedro J. Romero Service to JITC Award Recipient

The Society for Immunotherapy of Cancer (SITC) is proud to honor James L. Gulley, MD, PhD, FACP, as the recipient of the 2021 Pedro J. Romero Service to JITC Award. Nominated and selected by SITC colleagues in recognition of his commendable dedication to the journal and distinguished record of service, we extend our sincerest appreciation to Dr. Gulley for his significant contributions and outstanding commitment to JITC.


    2021 JITC Best Paper Award Recipients

    The journal proudly congratulates the JITC Best Paper Award recipients. Learn more about the outstanding original research selected in each of the five categories.

    Basic Tumor Immunology

    Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity

    Clinical/Translational Cancer Immunotherapy

    Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice

    Immune Cell Therapies and Immune Cell Engineering

    Development of a CD8 co-receptor independent T-cell receptor specific for tumor-associated antigen MAGE-A4 for next generation T-cell-based immunotherapy

    Immunotherapy Biomarkers

    Differential expansion of circulating human MDSC subsets in patients with cancer, infection and inflammation

    Oncolytic and Local Immunotherapy

    A systemically deliverable Vaccinia virus with increased capacity for intertumoral and intratumoral spread effectively treats pancreatic cancer


    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.

    Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project

    Diana M Merino, Lisa M McShane, David Fabrizio, Vincent Funari, Shu-Jen Chen, James R White, Paul Wenz, Jonathan Baden, J Carl Barrett, Ruchi Chaudhary, Li Chen, Wangjuh (Sting) Chen, Jen-Hao Cheng, Dinesh Cyanam, Jennifer S Dickey, Vikas Gupta, Matthew Hellmann, Elena Helman, Yali Li, Joerg Maas, Arnaud Papin, Rajesh Patidar, Katie J Quinn, Naiyer Rizvi, Hongseok Tae, Christine Ward, Mingchao Xie, Ahmet Zehir, Chen Zhao, Manfred Dietel, Albrecht Stenzinger, Mark Stewart, Jeff Allen

    Journal for ImmunoTherapy of Cancer 2020;8:e000147 (26 March 2020)


    Phase 2 study of pembrolizumab in patients with advanced rare cancers

    Aung Naing, Funda Meric-Bernstam, Bettzy Stephen, Daniel D Karp, Joud Hajjar, Jordi Rodon Ahnert, Sarina A Piha-Paul, Rivka R Colen, Camilo Jimenez, Kanwal P Raghav, Renata Ferrarotto, Shi-Ming Tu, Matthew Campbell, Linghua Wang, Sarjeel H Sabir, Coya Tapia, Chantale Bernatchez, Michael Frumovitz, Nizar Tannir, Vinod Ravi, Saria Khan, Jeane M Painter, Abulrahman Abonofal, Jing Gong, Anas Alshawa, Lacey M McQuinn, Mingxuan Xu, Sara Ahmed, Vivek Subbiah, David S Hong, Shubham Pant, Timothy A Yap, Apostolia M Tsimberidou, Ecaterina E Ileana Dumbrava, Filip Janku, Siqing Fu, Richard M Simon, Kenneth R Hess, Gauri R Varadhachary, Mouhammed Amir Habra

    Journal for ImmunoTherapy of Cancer 2020;8:e000347 (17 March 2020)


    A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors

    Aung Naing, Justin F Gainor, Hans Gelderblom, Patrick M Forde, Marcus O Butler, Chia-Chi Lin, Sunil Sharma, Maria Ochoa de Olza, Andrea Varga, Matthew Taylor, Jan H M Schellens, Hongqian Wu, Haiying Sun, Antonio P Silva, Jason Faris, Jennifer Mataraza, Scott Cameron, Todd M Bauer

    Journal for ImmunoTherapy of Cancer 2020;8:e000530 (15 March 2020)

    Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial

    Robert J Motzer, Bernard Escudier, David F McDermott, Osvaldo Arén Frontera, Bohuslav Melichar, Thomas Powles, Frede Donskov, Elizabeth R Plimack, Philippe Barthélémy, Hans J Hammers, Saby George, Viktor Grünwald, Camillo Porta, Victoria Neiman, Alain Ravaud, Toni K Choueiri, Brian I Rini, Pamela Salman, Christian K Kollmannsberger, Scott S Tykodi, Marc-Oliver Grimm, Howard Gurney, Raya Leibowitz-Amit, Poul F Geertsen, Asim Amin, Yoshihiko Tomita, M Brent McHenry, Shruti Shally Saggi, Nizar M Tannir

    Journal for ImmunoTherapy of Cancer 2020;8:e000891 (12 July 2020)

    SITC Members Receive 50 Percent Submission Discount in 2021

    *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 2021.