JITC Digest November 2022

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Inside this Issue:

Letter from the Editor

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Welcome to the latest edition of the JITC Digest, arriving in your inboxes just a few days after SITC’s 2022 Annual Meeting and Pre-Conference Programs. It was wonderful to see everybody in person and interact with so many of you, the JITC readers, during our meet the editor sessions, the journal’s 10th anniversary reception, and out around Boston.

If you were not able to attend the concurrent session on Friday dedicated to JITC’s high-impact science, I encourage you to catch up on the outstanding best paper award winners highlighted in this month’s special feature. Please also join me in extending heartfelt congratulations to the 2022 recipient of the Pedro J. Romero Service to JITC Award, Cornelis J.M. "Kees" Melief.

During her keynote address at SITC 2022, Padmanee Sharma described a model of iteration from clinical results to basic laboratory research that is then translated back to the clinic. JITC is proud to have supported this vital process over the past decade by publishing innovative science from across the basic science-translational-clinical spectrum, and we’re excited to help move our field forward for many more years in the future.

Our highlighted papers this month also span the basic science-translational-clinical spectrum, and include three original research articles and a case report.

Uncovering an underappreciated mechanism of immune dysfunction in the tumor microenvironment, Xia Liu and colleagues demonstrate that inhibition of DNA damage response signaling enhances the efficacy of PD-1 blockade by alleviating T cell senescence.

Enhanced T cell infiltration in both irradiated and non-irradiated lesions provides evidence for an abscopal effect with stereotactic body radiotherapy combined with pembrolizumab in a report from the phase II PEMBRO-RT trial from Lieke L van der Woude et al.

Xiaolu Yu and colleagues describe a novel PD-L1-directed nanobody conjugated to a toll-like receptor 7 agonist that induced complete regressions in murine models of early, established, and immunologically cold tumors.

Finally, Niklas Kehl and colleagues describe the first comprehensive genomic and immune profiling of IgE multiple myeloma, finding an unprecedentedly high mutation burden in this orphan disease and identifying neoepitopes that elicit autoreactive T cell responses.

I hope everyone’s travels returning home from Boston were smooth!

Best regards,

Pedro J. Romero, MD

Editor-in-Chief, Journal for ImmunoTherapy of Cancer


JITC Editor Picks

Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy

Xia Liu, Fusheng Si, David Bagley, Feiya Ma, Yuanqin Zhang, Yan Tao, Emily Shaw, Guangyong Peng
Journal for ImmunoTherapy of Cancer 2022;10:e005020 (3 October 2022)
RESEARCH
 
Summary:
Multiple mechanisms beyond exhaustion alone contribute to T cell dysfunction in the tumor microenvironment. Xia Liu and colleagues provide preclinical evidence that alleviation of T cell senescence via inhibition of AMK or MAPK signaling leads to enhanced antitumor efficacy of adoptive cell therapy and PD-1 blockade. In established murine breast, lung, and melanoma tumors, intratumoral, peripheral, and lymph node lymphocytes were positive for senescence-associated beta-galactosidase. While induced Tregs did not cause apoptosis or cell death, co-culture of CD4+ and CD8+ T cells with either tumor cells or induced Tregs resulted in populations of senescence-associated beta-galactosidase-positive cells as well as loss of lamin B1 expression. Consistent with previous studies linking the DNA damage response to senescence, lymphocytes isolated from tumor-bearing mice as well as co-cultured with tumor cells or induced Tregs had high levels of phosphorylation of ATM and its downstream targets H2AX and CHK2. Activation of MAPK signaling was also observed at high levels in T cells co-cultured with tumor cells or induced Tregs, evident as phosphorylated P38, ERK, and JNK. Pharmacologic inhibition of JNK, P38, and ERK1/2 alleviated loss of lamin B1 in senescent T cells in vitro. In mouse models of melanoma, pharmacologic inhibition of ATM or P38 alone had no effect on tumor growth. However, inhibition of ATM or P38 potentiated the anti-tumor effects of adoptive cell therapy, with even further inhibition of tumor growth as well as prolonged survival observed when anti-PD-1 was added. The findings reveal new insight into the myriad pathways underlying immune dysfunction in the tumor microenvironment, supporting further investigation of combination approaches targeting the DNA damage response or MAPK signaling with checkpoint inhibition.

Tumor microenvironment shows an immunological abscopal effect in patients with NSCLC treated with pembrolizumab-radiotherapy combinatio

Lieke L van der Woude, Mark A J Gorris, Inge M N Wortel, Jeroen H A Creemers, Kiek Verrijp, Kim Monkhorst, Katrien Grünberg, Michel M van den Heuvel, Johannes Textor, Carl G Figdor, Berber Piet, Willemijn S M E Theelen, I Jolanda M de Vries
Journal for ImmunoTherapy of Cancer 2022;10:e005433 (17 October 2022)
RESEARCH
 
Summary:
PEMBRO-RT was a randomized, phase II trial in which the addition of stereotactic body radiotherapy (SBRT) directed against a single lesion increased the overall response rate to pembrolizumab from 18% to 36% in patients with advanced non-small cell lung cancer. Reporting on treatment-associated changes in the tumor microenvironment in patients enrolled in PEMBRO-RT, Lieke L van der Woude and colleagues provide evidence that SBRT in combination with checkpoint blockade leads to enhanced T cell infiltration in both irradiated and non-irradiated lesions. Expectedly, both pembrolizumab alone and pembrolizumab in combination with SBRT resulted in significant increases in the total numbers of tumor-infiltrating lymphocytes after 6 weeks on treatment. Higher numbers of tumor-infiltrating lymphocytes at baseline was associated with response across both treatment groups. While total lymphocytic infiltration in non-irradiated sites increased post-treatment for both the pembrolizumab alone and the pembrolizumab plus SBRT groups, the fold change in intratumoral CD103+ cytotoxic T cells was roughly twice as high for the combination. The study establishes evidence that locally directed radiation in combination with checkpoint blockade can induce meaningful immunologic changes in distal lesions, consistent with an abscopal effect.

PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way

Carsten Krieg, Lukas M Weber, Bruno Fosso, Marinella Marzano, Gary Hardiman, Monica M Olcina, Enric Domingo, Sahar El Aidy, Khalil Mallah, Mark D Robinson, Silvia Guglietta
Journal for ImmunoTherapy of Cancer 2022;10:e004717 (22 September 2022)
RESEARCH
 
Summary:
Toll-like receptor 7 (TLR7) agonism activates antigen-presenting cells resulting in T cell activation as well as intratumoral infiltration of natural killer cells and tumor antigen-specific interferon-secreting effector cells. Xiaolu Yu and colleagues demonstrate potent anti-tumor activity in multiple pre-clinical models for a novel PD-L1-directed nanobody coupled to a TLR7 agonist. In murine CT26 colon cancer models, treatment with the nanobody-TLR7 agonist conjugate impaired tumor growth for both early and established tumors, with mice that achieved complete regressions rejecting rechallenge for more than 40 days. Immunophenotyping revealed maturation of dendritic cells, repolarization of tumor-associated macrophages and increased PD-L1 expression on macrophages upon treatment with the nanobody-TLR7 agonist conjugate. Strikingly, although treatment with the nanobody conjugate resulted in upregulation of PD-L1 on tumor cells and intratumoral leukocytes, expression on peripheral blood and spleen cells was downregulated as dosing progressed. Host PD-L1 was required for tumor control, but knockout of PD-L1 in tumor cells did not impair efficacy nor upregulation of PD-L1 on intratumoral macrophages with treatment. Safety evaluations revealed no evidence of pathological damage to organs of concern nor abnormalities in hematology or plasma chemistry parameters. This preclinical evidence highlights the potential of nanobodies as a platform technology for directly targeting immune exhaustion within the tumor microenvironment while simultaneously enhancing T cell infiltration to immunologically cold tumors via delivery of innate immune agonists.

IgE type multiple myeloma exhibits hypermutated phenotype and tumor reactive T cells

Niklas Kehl, Michael Kilian, Julius Michel, Tim R Wagner, Sebastian Uhrig, Alexander Brobeil, Lilli-Sophie Sester, Sven Blobner, Simon Steiger, Michael Hundemer, Niels Weinhold, Karsten Rippe, Stefan Fröhling, Stefan B Eichmüller, Lukas Bunse, Carsten Müller-Tidow, Hartmut Goldschmidt, Michael Platten, Marc-Steffen Raab, Mirco J Friedrich
Journal for ImmunoTherapy of Cancer 2022;10:e004590 (17 October 2022)
SHORT REPORT
 
Summary:
IgE type multiple myeloma is a highly aggressive and rare subtype of the plasma cell malignancy that is associated with a very poor prognosis. Integrating DNA and single cell-RNA sequencing, Niklas Kehl and colleagues describe the first comprehensive genomic and immune profiling of IgE multiple myeloma. A male patient in his late 30s with standard risk cytogenetics and multiple osteolytic bone lesions received initial treatment with four cycles of bortezomib, cyclophosphamide, and dexamethasone, followed by tandem high dose melphalan therapy and autologous stem cell transplantation and lenalidomide/dexamethasone maintenance and had a best response of stable disease with early relapse 12 months after completion of therapy. IgE type multiple myeloma cells from bone marrow aspirates displayed a distinct transcriptional profile compared to published datasets from non-IgE type myeloma cells. Although the overall abundance of individual subsets of tumor-infiltrating lymphocytes did not differ between this case of IgE type multiple myeloma and the comparison cohort of non-IgE type myelomas, a hyperexpanded T cell repertoire of effector and cytotoxic T cells was identified. Strikingly, this case of IgE type multiple myeloma had the highest tumor mutation burden of multiple myeloma genomes analyzed, with 5.0 non-synonymous mutations per coding megabase. Among the 124 peptides identified as potential neoepitopes via haplotyping, somatic variant calling, and MHC class I binding prediction, four motifs were identified that elicited T cell cytokine responses in vitro, of which two were identified as highly expressed in IgE type multiple myeloma. Although the generalizability of this single case may be limited, these data emphasize the value of next-generation sequencing techniques to provide potentially actionable therapeutic insights for rare diseases and provide a conceptual foundation for future exploration of personalized adoptive cell therapy approaches.


View other articles from this issue


    

JITC Award Recipients

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Congratulations to Cornelis J.M. “Kees” Melief, MD, PhD, the recipient of this year’s Pedro J. Romero Service to JITC Award. Nominated and selected by Society for Immunotherapy of Cancer (SITC) colleagues in recognition of his commendable dedication to the journal and distinguished record of service, Dr. Melief has made innumerable contributions to JITC and the immuno-oncology field.

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Cornelis J.M. “Kees” Melief, MD, PhD
Leiden University Medical Center & ISA Pharmaceuticals (The Netherlands)
   
   

2022 JITC Best Paper Award Recipients

Congratulations to the 2022 JITC Best Paper Award recipients, a number of whom presented rapid oral abstracts on their award-winning papers during the SITC Annual Meeting at Session 207: A Look at JITC's High-Impact Science.

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View the complete list of 2022 JITC Best Paper Award recipients here.



Popular Archive Articles

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In honor of many of the 2022 SITC Award recipients and this year’s inductees into SITC’s Academy of Immuno-Oncology, the selections below spotlight some of their recent works published in JITC, and represent some of the most popular content from 2021 and 2022 in the journal. 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. 

Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial

Robert L Ferris, William C Spanos, Rom Leidner, Anthony Gonçalves, Uwe M Martens, Chrisann Kyi, William Sharfman, Christine H Chung, Lot A Devriese, Helene Gauthier, Simon I Chiosea, Lazar Vujanovic, Janis M Taube, Julie E Stein, Jun Li, Bin Li, Tian Chen, Adam Barrows, Suzanne L Topalian
Journal for ImmunoTherapy of Cancer 2021;9:e002568 (2 June 2021)RESEARCH


DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma

Allison A Fitzgerald, Shangzi Wang, Veena Agarwal, Emily F Marcisak, Annie Zuo, Sandra A Jablonski, Melanie Loth, Elana J Fertig, John MacDougall, Eugene Zhukovsky, Shubhendu Trivedi, Dimple Bhatia, Vince O'Neill, Louis M Weiner
Journal for ImmunoTherapy of Cancer 2021;9:e002837 (4 November 2021)
RESEARCH

Peptide emulsions in incomplete Freund’s adjuvant create effective nurseries promoting egress of systemic CD4+ and CD8+ T cells for immunotherapy of cancer

Marit M Melssen, Caroline T Fisher, Craig L Slingluff and Cornelis J M Melief
Journal for ImmunoTherapy of Cancer 2022;10:e004709 (9 September 2022)
REVIEW

Maximizing the value of phase III trials in immuno-oncology: A checklist from the Society for Immunotherapy of Cancer (SITC)

Michael B Atkins, Hamzah Abu-Sbeih, Paolo A Ascierto, Michael R Bishop, Daniel S Chen, Madhav Dhodapkar, Leisha A Emens, Marc S Ernstoff, Robert L Ferris, Tim F Greten, James L Gulley, Roy S Herbst, Rachel W Humphrey, James Larkin, Kim A Margolin, Luca Mazzarella, Suresh S Ramalingam, Meredith M Regan, Brian I Rini, Mario Sznol
Journal for ImmunoTherapy of Cancer 2022;10:e005413 (29 September 2022)
POSITION ARTICLES AND GUIDELINES

From the Vault

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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. This month’s From the Vault takes a look at some of the top articles in JITC authored by 2022 SITC Award recipients and this year’s inductees into SITC’s Academy of Immuno-Oncology

High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014

Stefani Spranger, Holly K. Koblish, Brendan Horton, Peggy A. Scherle, Robert Newton and Thomas F. Gajewski Journal for ImmunoTherapy of Cancer 2014 2:3 (18 February 2014) REVIEW

Multispectral imaging of formalin-fixed tissue predicts ability to generate tumor-infiltrating lymphocytes from melanoma

Zipei Feng, Sachin Puri, Tarsem Moudgil, William Wood, Clifford C. Hoyt, Chichung Wang, Walter J. Urba, Brendan D. Curti, Carlo B. Bifulco and Bernard A. Fox Journal for ImmunoTherapy of Cancer 2015 3:4 (20 October 2015) RESEARCH

Novel technologies and emerging biomarkers for personalized cancer immunotherapy

Jianda Yuan, Priti S Hegde, Raphael Clynes, Periklis G Foukas, Alexandre Harari, Thomas O Kleen, Pia Kvistborg, Cristina Maccalli, Holden T Maecker, David B Page, Harlan Robins, Wenru Song, Edward C Stack, Ena Wang, Theresa L Whiteside, Yingdong Zhao, Heinz Zwierzina, Lisa H Butterfield & Bernard A Fox
Journal for ImmunoTherapy of Cancer 2016;4:3 (19 January 2016)
 
REVIEW

Mechanisms regulating PD-L1 expression on tumor and immune cells

Patrick Danaher, Sarah Warren, Rongze Lu, Josue Samayoa, Amy Sullivan, Irena Pekker, Brett Wallden, Francesco M. Marincola, and Alessandra Cesano Journal for ImmunoTherapy of Cancer 2018, 6:63 (22 June 2018) RESEARCH

SITC Members Receive a 50 Percent Discount on Article Processing Charges in 2022
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 article processing fees for all JITC articles accepted in 2022.
 
Become a SITC Member Today!

JITC also offers waivers for the APC (100% discount of the APC) where all authors are based in low-income countries (see policy). Requests for waivers must be made prior to submission. For additional information regarding these discounts, as well as institutional arrangements, view the journal's APC policy. Additional questions may be directed to JITCEditor@sitcancer.org.