JITC Digest May 2022


Inside this Issue:

Letter from the Editor

Dear JITC Readers,pedro-romero_1__1_.jpg

This month’s JITC digest marks the beginning of the journal’s 10th anniversary year. Since our first issue was published in May of 2013, the journal and the immunotherapy field have evolved tremendously and we are excited to continue supporting the advancement of the immuno-oncology discipline for many years to come.

We hope you will join us in celebrating a decade of JITC. Take a walk down memory lane with us by exploring the special features on our 10th anniversary page, including an editorial looking back on the journal’s storied history as well as an illuminating fireside chat between SITC President Dr. Patrick Hwu and JITC leadership on the journal’s trajectory.

Throughout the past 10 years, JITC has published innovative research from across the immunotherapy field. This month, the papers highlighted in the digest emphasize how even such a familiar topic as PD-1 blockade still yields novel insights with clinical and translational data on novel combination strategies, biomarkers, and response dynamics.

Acceptable safety with response rates of around 35% are reported by Charu Aggarwal et al in a phase I/II trial evaluating the combination of anti-PD-1 and anti-B7-H3 in checkpoint inhibitor-naïve head and neck and non-small cell lung cancers.

Yongxiang Xia and colleagues describe efficacy and safety for perioperative anti-PD-1 plus anti-VEGF TKI for hepatocellular carcinoma as well as ctDNA-based biomarkers for predicting response and recurrence risk with the combination.

An inverse association between somatic copy number alteration burden, immune cell infiltration, and progression-free survival in non-small cell lung cancer is revealed by Joan Frigola and colleagues.

Finally, Yoon-Koo Kang et al find no evidence for hyperprogression in patients with gastric cancer or small-cell lung cancer treated with checkpoint blockade in the first analysis of the phenomenon using data from randomized controlled trials.

No matter whether you’ve been with us from the beginning or have just recently discovered JITC, we’re grateful for all our readers and we’re excited for what the future has in store for the journal and our field.


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

JITC Editor Picks

Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial

Charu Aggarwal, Amy Prawira, Scott Antonia, Osama Rahma, Anthony Tolcher, Roger B Cohen, Yanyan Lou, Ralph Hauke, Nicholas Vogelzang, Dan P Zandberg, Arash Rezazadeh Kalebasty, Victoria Atkinson, Alex A Adjei, Mahesh Seetharam, Ariel Birnbaum, Andrew Weickhardt, Vinod Ganju, Anthony M Joshua, Rosetta Cavallo, Linda Peng, Xiaoyu Zhang, Sanjeev Kaul, Jan Baughman, Ezio Bonvini, Paul A Moore, Stacie M Goldberg, Fernanda I Arnaldez, Robert L Ferris, Nehal J Lakhani
Journal for ImmunoTherapy of Cancer 2022;10:e004424 (12 April 2022)



B7-H3 (CD276) is an immune checkpoint that inhibits T cell activation and cytokine production with broad surface expression on many malignant neoplasms and minimal expression on normal tissues. In a phase I/II trial, Charu Aggarwal and colleagues report meaningful antitumor activity with combination anti-B7-H3 and pembrolizumab in patients with a variety of solid tumors. Treatment with combination pembrolizumab and enoblituzumab (a B7-H3-specific monoclonal antibody Fc-optimized for enhanced antibody-dependent cell mediated cytotoxicity) led to an overall response rate (ORR) of 33.3% in 21 patients with head and neck squamous cell carcinoma (HNSCC) who were anti-PD-1-naïve. No responses were observed for 24 patients with HNSCC who had prior anti-PD-(L)1, yet 47% (n = 9) had disease stabilization with a median duration of disease control of 3.55 months. Similar trends were seen in patients with non-small cell lung cancer—the ORR in 16 anti-PD-(L)1-naïve patients was 35.7% and among 21 evaluable patients with prior anti-PD-(L)1 there were 2 who had partial responses and 11 with stable disease with a median duration of response of 3.45 months. Benefit was independent of PD-L1 expression. Limited responses were seen in cohorts of patients with melanoma and urothelial cancer who had previously received anti-PD-(L)1. The safety profile was acceptable, with the majority of adverse events being grade 1 and 2. One treatment-related death due to pneumonitis occurred. The results support further evaluation of safety and efficacy for the combination of pembrolizumab and enoblituzumab in anti-PD-(L)1-naïve tumors.

Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trial

Yongxiang Xia, Weiwei Tang, Xiaofeng Qian, Xiangcheng Li, Feng Cheng, Ke Wang, Feng Zhang, Chuanyong Zhang, Donghua Li, Jinhua Song, Hui Zhang, Jie Zhao, Aihua Yao, Xiaofeng Wu, Chen Wu, Guwei Ji, Xisheng Liu, Feipeng Zhu, Lang Qin, Xuan Xiao, Zhenhua Deng, Xiangyi Kong, Si Li, Yangyang Yu, Wenjing Xi, Wanglong Deng, Chuang Qi, Hanyuan Liu, Liyong Pu, Ping Wang, Xuehao Wang
Journal for ImmunoTherapy of Cancer 2022 (3 April 2022)



Consolidation therapy with the anti-PD-L1 durvalumab after chemoradiation is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC), but response rates are less than 30% and robust biomarkers to predict clinical benefit are lacking. Hypothesizing that subvisual features of pre-treatment NSCLC tumors on CT imaging may correspond to physiologic characteristics that increase likelihood of recurrence, Khalid Jazieh and colleagues developed a radiomic risk score to predict progression free survival (PFS) and overall survival (OS) after durvalumab consolidation. In training and validation sets that each included 59 patients with unresectable stage III NSCLC who received durvalumab consolidation, low pre-treatment radiographic risk scores were associated with significantly improved PFS and OS. High radiomic risk score was also associated with worse PFS and OS in a separate cohort of 15 patients that received chemoradiotherapy alone. High radiographic risk score was associated with worse PFS regardless of tumor PD-L1 expression status. For OS, however, a low radiographic risk score only corresponded with improved survival outcomes in the patients with tumor PD-L1 expression less than 50%. Decision curve analysis demonstrated that an integrated radiomic risk score and clinical model had the highest net benefit in identifying patients who should receive consolidation durvalumab. With further validation, CT image-derived radiomic biomarkers may provide a minimally invasive decision support tool for consideration of risks versus benefits of immunotherapy.

High levels of chromosomal aberrations negatively associate with benefit to checkpoint inhibition in NSCLC

Joan Frigola, Caterina Carbonell, Patricia Irazno, Nuria Pardo, Ana Callejo, Susana Cedres, Alex Martinez-Marti, Alejandro Navarro, Mireia Soleda, Jose Jimenez, Javier Hernandez-Losa, Ana Vivancos, Enriqueta Felip, Ramon Amat
Journal for ImmunoTherapy of Cancer 2022; (27 April 2022)



Tumors with high levels of aneuploidy are known to be poorly immune-infiltrated. While overall tumor mutation burden has been well-characterized as a predictor of response to PD-1 blockade in some settings, the effects of gains or losses of specific genomic loci or regions on immunotherapy response are incompletely understood. Using “shallow” whole-genome sequencing in samples from non-small cell lung cancer (NSCLC) tumors, Joan Frigola and colleagues demonstrate an association between somatic copy number alterations and progression-free survival (PFS) with checkpoint blockade. Across samples from 77 patients with NSCLC who received checkpoint inhibitor therapy in the first, second, or subsequent line of therapy, somatic copy number alterations affected an average of 45% of the genome. The overall number of somatic copy number alterations was not statistically significantly associated with PFS, however, the fraction of the genome altered was inversely correlated with survival. Notably, the burden of copy number alterations affecting less than 50% of a chromosome arm was not associated with PFS benefit—the biomarker with the best predictive value was the fraction of the genome altered by events affecting more than 50% of a single chromosome arm combined with those affecting both chromosome arms and encompassing at least 50% of the entire chromosome. The association between the fraction of the genome-altered score and PFS with checkpoint blockade remained significant across smoking status, histology, primary or metastatic site, and patient sex, although the effect size was greater for female patients. In the patient samples as well as analysis of The Cancer Genome Atlas, higher fractions of the genome altered by somatic copy number variations were associated with decreased immune cell infiltration by gene expression profiling signatures.

Assessment of hyperprogression versus the natural course of disease development with nivolumab with or without ipilimumab versus placebo in phase III, randomized, controlled trials

Yoon-Koo Kang, Martin Reck, Paul Nghiem, Yan Feng, Gregory Plautz, Hye Ryun Kim, Taofeek K Owonikoko, Narikazu Boku, Li-Tzong Chen, Ming Lei, Han Chang, Wen Hong Lin, Amit Roy, Akintunde Bello, Jennifer Sheng
Journal for ImmunoTherapy of Cancer 2022;10:e004273 (5 April 2022)


Hyperprogression, an apparent acceleration of tumor growth after treatment with anti-PD-(L)1 checkpoint blockade has been reported in single-arm retrospective studies, but it remains unclear whether a sudden acceleration in tumor growth on treatment represents an atypical response to immunotherapy or the natural course of disease. In the first analysis of its kind using randomized trial data, Yoon-Koo Kang and colleagues find no evidence for hyperprogression in patients receiving nivolumab monotherapy or nivolumab plus ipilimumab. Because serial pre-treatment scans were not available to calculate tumor growth rate, hyperprogression was defined based on percentage change from baseline in target lesion sum of the longest diameters across multiple cut-offs. A total of 358 patients from ATTRACTION-2 (243 received nivolumab and 115 placebo) and 531 patients from CheckMate 415 (177 received nivolumab monotherapy, 179 nivolumab plus ipilimumab, and 175 placebo) had baseline and first post-treatment scans available for analysis. In both CheckMate 415 and ATTRACTION-2, the numbers of patients who had sum of target lesion diameter increases of greater than 50% or 20% were lower in the immunotherapy arms compared to the placebo arms. The small numbers of patients who had tumor growth greater than 100% were similar across placebo and immunotherapy arms for both trials. Greater than 20% increase in tumor size from baseline was significantly associated with worse overall survival in both trials. No obvious association between MDM2/MDM4 amplification and hyperprogression was identified in either study population, but the number of tumors harboring alterations was small. The findings suggest that rare cases of rapid growth on treatment may be attributable to intrinsic tumor biology as opposed to an unknown mechanism induced by checkpoint blockade.  

view other articles from this issue

JITC-10th-Anniversary.jpgAs JITC enters its 10th year of publishing this month, we invite you to join us in celebrating the occasion. Leaders of SITC and JITC have launched the celebration with a new editorial that illuminates the tremendous growth of JITC and how significant events have shaped the rapidly evolving tumor immunology and cancer immunotherapy fields over the past ten years.

Learn more about JITC’s evolution, including important milestones and high-impact content, on the journal’s special 10th anniversary webpage.

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. To get things started, this month’s From the Vault takes a look at some top papers that have published over time to the journal’s four founding sections: Basic Tumor Immunology, Clinical/Translational Cancer Immunotherapy, Immunotherapy Biomarkers, and Reviews.

Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8+ T cells directly within the tumor microenvironment

Stefani Spranger, Holly K. Koblish, Brendan Horton, Peggy A. Scherle, Robert Newton, and Thomas F. Gajewski
Journal for ImmunoTherapy of Cancer 2020;2(1)3 (18 February 2014)
Basic Tumor Immunology

Gene expression markers of Tumor Infiltrating Leukocytes

Patrick Danaher, Sarah Warren, Lucas Dennis, Leonard D’Amico, Andrew White, Mary L. Disis, Melissa A. Geller, Kunle Odunsi, Joseph Beechem, Steven P. Fling
Journal for ImmunoTherapy of Cancer 2017;5(1)18 (21 February 2017)
Immunotherapy Biomarkers

Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after >/= 1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial

Howard L. Kaufman, Jeffery S. Russell, Omid Hamid, Shailender Bhatia, Patrick Terheyden, Sandra P. D’Angelo, Kent C. Shih, Céleste Lebbé, Michele Milella, Isaac Brownell, Karl D. Lewis, Jochen H. Lorch, Anja von Heydebreck, Meliessa Hennessy, Paul Nghiem
Journal for ImmunoTherapy of Cancer 2017;6(1)17 (19 January 2018)

Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

Jun Gong, Alexander Chehrazi-Raffle, Srikanth Reddi, Ravi Salgia
Journal for ImmunoTherapy of Cancer 2018; (23 January 2018)


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.

Identification of tumor immune infiltration-associated lncRNAs for improving prognosis and immunotherapy response of patients with non-small cell lung cancer

Jie Sun, Zicheng Zhang, Siqi Bao, Congcong Yan, Ping Hou, Nan Wu, Jianzhong Su, Liangde Xu, Meng Zhou
Journal for ImmunoTherapy of Cancer 2020;8:e000110 (10 February 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)

Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial

Sandra P D'Angelo, Shailender Bhatia, Andrew S Brohl, Omid Hamid, Janice M Mehnert, Patrick Terheyden, Kent C Shih, Isaac Brownell, Celeste Lebbé, Karl D Lewis, Gerald P Linette, Michele Milella, Sara Georges, Parantu Shah, Barbara Ellers-Lenz, Marcis Bajars, Gülseren Güzel, Paul T Nghiem
Journal for ImmunoTherapy of Cancer 2020;8:e000674 (15 May 2020)

Targeting immunogenic cancer cell death by photodynamic therapy: past, present and future

Razan Alzeibak, Tatiana A. Mishchenko, Natalia Y. Shilyagina, Irina V. Balalaeva, Maria V. Vedunova, Dmitri V. Krysko
Journal for ImmunoTherapy of Cancer 2021;8:e001926 (11 January 2021)

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.