JITC Digest November 2024

By JITC Publications posted 11-20-2024 09:58

INSIDE THIS ISSUE:

Letter from the Editor | JITC Editor Picks | New Special Series | 2024 JITC Mentorship Program Graduates | Popular Archive Articles

Letter from the Editor

Hello JITC Readers,

Welcome to this month’s JITC Digest, coming your way less than two weeks after the conclusion of SITC’s 2024 Annual Meeting and Pre-Conference Programs. It was a pleasure seeing so many of you in Houston, whether we were attending sessions, chatting through the concourses, stretching our legs at the 5K fun run, or dancing the night away with the Checkpoints on Saturday!

Personal highlights included the Meet-the-Editor session, during which a group of JITC readers spent more than an hour discussing their work with me. It was wonderful to see the enthusiasm of young researchers and their interest in JITC. I also send a heartfelt congratulations to the numerous recipients of JITC and SITC awards and recognition, including the 2024 JITC Best Paper Award recipients, the 28 graduates of this year’s JITC Peer Review Mentorship Program, as well as Andrea Kunz, who received the “Pedro J. Romero Service to JITC Award.” Congratulations to you all on your outstanding work and dedication to JITC and the field.

I also watched with great interest Dr. Elizabeth Jaffee’s keynote address, “The Era of Cancer Vaccines Has Arrived.” With that, I am proud to announce her recent publication in JITC, “Pancreatic cancer is feeling the heat,” which represents the first in a special series of commentaries that will publish in our journal over the next year in celebration of the upcoming 40^th anniversary of SITC. Stay tuned for more additions to the series! We also recently saw the first publications in another new series, “Cancer Immunotherapy in Understudied Populations,” led by Guest Editors Drs. Kavita Dhodapkar and Johanneke E. A. Portielje. I encourage you to read these first publications and check back for more articles to come.

As for recent original research articles in JITC, highlights for this month include results from a preclinical study conducted by Takayuki Kamikawa and colleagues, characterizing the activity and pharmacodynamics profile of a novel trispecific antibody, SAIL66, for the treatment of patients with ovarian cancer. Targeting Claudin-6 and CD3/CD137, SAIL66 demonstrated decreased T cell exhaustion, increased T cell infiltration, and greater anti-tumor activity in vivo relative to a bispecific Claudin-6 T cell engager, providing support for a phase I clinical study (NCT05735366).

Additionally, Marta Molina-Alejandre et al investigated the association between HLA class I loss of heterozygosity and clinical outcomes in response to chemoimmunotherapy in patients with resectable non-small cell lung cancer. Though HLA-proficient tumors were more immune infiltrated, surprisingly there were no differences in tumor mutational burden, survival outcomes, or complete pathological response rates between HLA-proficient and HLA-deficient tumors when treated with chemoimmunotherapy.

I hope everyone had smooth travels back home from Houston, and if we didn’t get the opportunity to meet, I look forward to celebrating 40 years of SITC with you next year in National Harbor, MD!

Regards,

Michael T. Lotze, MD
Editor-in-Chief
Journal for ImmunoTherapy of Cancer

JITC Editor Picks

SAIL66, a next generation CLDN6-targeting T-cell engager, demonstrates potent antitumor efficacy through dual binding to CD3/CD137

Takayuki Kamikawa, Naoki Kimura, Shinya Ishii, Masaru Muraoka, Tatsushi Kodama, Kenji Taniguchi, Moe Yoshimoto, Momoko Miura-Okuda, Ryo Uchikawa, Chie Kato, Junko Shinozuka, Sho Akai, Sotaro Naoi, Nanami Tomioka, Nishiki Nagaya, Chai Ling Pang, Gupta Garvita, Shu Feng, Mei Shimada, Mika Kamata-Sakurai, Hiroyuki Aburatani, Takehisa Kitazawa, Tomoyuki Igawa
Journal for ImmunoTherapy of Cancer 2024;12:e009563 (14 October 2024)
RESEARCH

Summary:

Bispecific T cell engagers (TCEs) can promote tumor killing independent of immunogenicity, providing a promising therapeutic strategy for tumors resistant to immune checkpoint inhibition. However, these TCEs often suffer from “on-target/off-tumor” toxicity and T cell exhaustion due to chronic CD3 activation without subsequent co-stimulation. This preclinical study investigated the antitumor activity and pharmacodynamic profile of SAIL66, a novel trispecific antibody targeting CD3/CD137 and Claudin-6 (CLDN6), a tight junction molecule overexpressed in ovarian cancer. Binding studies revealed high specificity of SAIL66 for CLDN6 relative to other CLDN molecules. In vitro studies comparing SAIL66 versus a bispecific CLDN6 TCE incubated the TCEs with T cells from peripheral blood mononuclear cells and CLDN-6 expression cancer cell lines and found that SAIL66 induced a significantly stronger T cell response and cytokine release directed toward the cancer cells compared to the bispecific TCE. Additionally, in a humanized mouse model (huNOG), SAIL66 treatment demonstrated decreased T cell exhaustion, increased T cell infiltration, and greater anti-tumor activity over CLDN6 TCE treatment. These data overcome many challenges with traditional bispecifics, and provide rationale for the use of SAIL66 in an early clinical study (NCT05735366).

Perioperative chemoimmunotherapy induces strong immune responses and long-term survival in patients with HLA class I-deficient non-small cell lung cancer

Marta Molina-Alejandre, Francisco Perea, Virginia Calvo, Cristina Martinez-Toledo, Ernest Nadal, Belén Sierra-Rodero, Marta Casarrubios, Joaquín Casal-Rubio, Alex Martinez-Martí, Amelia Insa, Bartomeu Massuti, Santiago Viteri, Isidoro Barneto Aranda, Delvys Rodriguez-Abreu, Javier de Castro, Joaquín Mosquera Martínez, Manuel Cobo, Ignacio I Wistuba, Edwin R Parra, Javier Martín-López, Diego Megías, Rafael Muñoz-Viana, Federico Garrido, Natalia Aptsiauri, Francisco Ruiz-Cabello, Mariano Provencio, Alberto Cruz-Bermúdez
Journal for ImmunoTherapy of Cancer 2024;12:e009762 (20 October 2024)
RESEARCH

Summary:

Alterations in human leukocyte antigen (HLA) class I expression patterns represent important immune escape mechanisms used by tumors that are associated with poor prognosis and poor response to immunotherapy. However, the role of HLA class I in eliciting response to perioperative chemoimmunotherapy (ChIO) treatment of non-small cell lung cancer (NSCLC) remains unclear. This study evaluated the HLA class I status and other tumor characteristics of 24 patients with resectable NSCLC enrolled in the NADIM trial (NCT03081689) who received perioperative ChIO. Though HLA-proficient (HLA-PRO) tumors had significantly higher PD-L1 expression (p=0.004) and immune infiltration than HLA-deficient (HLA-DEF) tumors, there was no difference in tumor mutational burden (TMB) (p=0.987), 3-year progression-free survival (p=0.909), 3-year overall survival (p=0.137) or complete pathological response (CPR) rates (p=0.67). Additionally, the HLA-DEF tumors that had CPR formed tertiary lymphoid structures (TLS) that were not seen in HLA-DEF tumors that did not experience CPR. These findings highlight the potential role of TLS formation in driving effective immunotherapy response in HLA-DEF NSCLC tumors.

Leveraging mitochondrial-programmed cell death dynamics to enhance prognostic accuracy and immunotherapy efficacy in lung adenocarcinoma

Lianmin Zhang, Yanan Cui, Guangyao Zhou, Zhenfa Zhang, Pengpeng Zhang
Journal for ImmunoTherapy of Cancer 2024;12:e010008 (24 October 2024)
RESEARCH

Summary:

Despite the success of immunotherapy for many patients, survival rates remain low for lung adenocarcinoma (LUAD), a highly complex tumor requiring more accurate prognostic predictions to help guide personalized treatment. This study combined transcriptomic data, histology, and clinical data from The Cancer Genome Atlas (TCGA) to develop a mitochondrial-related programmed cell death signature (MPCDS) to predict prognosis in LUAD patients. This machine learning approach successfully predicted treatment outcomes in melanoma, clear cell renal cell carcinoma, and LUAD cohorts, with improved performance over 114 existing LUAD models. Increased expression of a key gene incorporated into the MPCDS, nucleoside diphosphate kinase 4 (NME4), was associated with poor prognosis in immune-excluded tumors. Furthermore, in vitro proliferation/migration assays, and in vivo analysis of immune checkpoint blockade (ICB) in a NME4 knockout xenograft mouse model revealed enhanced CD8⁺T cell activity and greater antitumor immunity with NME4 inhibition, improving the efficacy of ICB. The MPCDS offers promising support for the role of machine learning in personalized risk assessment for patients with LUAD while also highlighting NME4 as a novel target for immunotherapy.

Dendritic cell-intrinsic PTPN22 negatively regulates antitumor immunity and impacts anti-PD-L1 efficacy

Santiago Acero-Bedoya, Emily F Higgs, Anna C Martinez, Ruxandra Tonea, Thomas F Gajewski
Journal for ImmunoTherapy of Cancer 2024;12:e009588 (26 October 2024)RESEARCH

Summary:

Patients with a loss-of-function single-nucleotide polymorphism (SNP) in the PTPN22 gene exhibit an increased risk for autoimmune diseases, but are also more likely to respond to immune checkpoint blockade (ICB). This study sought to further understand the relationship between PTPN22 in dendritic cells (DCs) and the development of immune responses. The deletion of PTPN22 in CD11c+ DCs in a conditional knockout (cKO) mouse model enhanced tumor control in multiple tumor models, exhibiting increased tumor antigen-specific CD8+ T cells in the tumor microenvironment (TME). This response was CD8+ T cell-dependent and linked to enhanced T cell priming in the draining lymph nodes. Increased DC proliferation in response to Flt3L and improved antigen processing/presentation were observed in vitro and in vivo. PTPN22 cKO mice also showed improved response to anti-PD-L1 therapy relative to wildtype mice. These results suggest a role for PTPN22 in modulating DC function and response to immunotherapy, providing support for PTPN22 as a potential therapeutic target for enhancing antitumor immunity.

Two New Special Series

JITC is proud to announce the first publications in a new series, “Cancer Immunotherapy in Understudied Populations.” Authored by leading voices from diverse backgrounds, “Cancer Immunotherapy in Understudied Populations” highlights issues that impact aging- and DEI-related research in the current immuno-oncology landscape and aims to inspire researchers who will fill knowledge gaps in immunotherapy with respect to the roles of aging, race, ethnicity and social determinants of health.

Edited by Kavita Dhodapkar, MBBS, and Johanneke E. A. Portielje, MD, PhD, “Cancer Immunotherapy in Understudied Populations” covers various aspects of understudied demographics and addresses immunotherapy treatments, both for solid cancers and hemato-oncology, and immune response among these groups.

Check the collection throughout 2024 for new publications.

SITC 40th Anniversary: I-O Progress and Potential

JITC is also pleased to present a new special series of commentaries from luminaries in the field of immuno-oncology in celebration of the 40^th Anniversary of SITC. Fellows of the Academy of Immuno-Oncology and Richard V. Smalley Memorial Award recipients come together in a special series of commentaries that provides insights into achievements in I-O while also sharing their personal, forward-looking visions for the path ahead.

Get an early look at what is ahead for the series by reading the first commentary, authored by 2024 Richard V. Smalley Award recipient Elizabeth Jaffee, and be sure to check the collection throughout 2025 for more publications. “SITC 40^th Anniversary: I-O Progress and Potential” will form a roadmap to the future of I-O that touches on areas of opportunity while also celebrating 40 years of SITC driving breakthroughs in cancer immunotherapy.

**2024 JITC Peer Review Mentorship Program Graduates**

Congratulations to the JITC Peer Review Mentorship Program Graduates who completed the 2024 program, reviewing one manuscript approximately every six weeks with their mentors January–September:

Carmen Aguilar-Gurrieri, PhD
Benedict Boateng Antuamwine, PhD
Tsolere Arakelian, PhD
Sachin Chauhan, PhD
David Chen, MD
Yingshi Chen, MD
Stacey Doran, MD
Guilia Escobar, PhD
Constance Fourny

Sagnik Giri, PhD
Ana Karen Gutierrez Garcia, PhD
Leila Haghani, PhD
Shabbir Hussain, MD
Esin Aysel Kandemir
Calvin Lam
Myrto Moutafi, MD
Aleksander Murgaski, PhD
Saifun Nahar, MD, PhD

Muhammad Saeed, PhD
Anna Salamero Boix
R. Alejandro Sica, MD
Rio Sugimura, MD, PhD
Vijay Ulaganathan, PhD
Marit van Elsas, PhD
Wes Wilson, PhD
Junzhe (Jacky) Zhao
Yao Zhu, MD, PhD

JITC also sends its sincere gratitude and appreciation to the 2024 mentors for their generous time and commitment to the program, providing structural guidance on peer review:

Esra Akbay, PhD
Pedro Berraondo, PharmD, PhD
Praveen Bommareddy, PhD
Alessio Cortellini, MD, PhD
Julia Cuende, PhD
Noel de Miranda, PhD
Sofia Gameiro, PhD
Francois Ghiringhelli, PhD
Hongbo Hu, PhD
Oliver Kepp, PhD

Khashayarsha Khazaie, PhD DSc
Yangqiu Li, MD
Il Minn, PhD
Paola Nistico, MD
Takayuri Ohkuri, PhD
Ravi Patel, MD, PhD
Graham Pawelec, PhD
Nirali Shah, MD
Walter Storkus, PhD
Thorbald van Hall, PhD

Learn more about the Peer Review Mentorship Program and how to become a volunteer reviewer for JITC.

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