Blogs

Cell membrane-anchored and tumor-targeted IL-12 T-cell therapy destroys cancer-associated fibroblasts and disrupts extracellular matrix in heterogenous osteosarcoma xenograft models

Jiemiao Hu, Alexander J Lazar, Davis Ingram, Wei-Lien Wang, Wendong Zhang, Zhiliang Jia, Dristhi Ragoonanan, Jian Wang, Xueqing Xia, Kris Mahadeo, Richard Gorlick, Shulin Li
Journal for ImmunoTherapy of Cancer 2024;12:e006991 (9 January 2024)

RESEARCH

Summary:

Osteosarcoma has a rich extracellular matrix (ECM), and ECM components such as cancer-associated fibroblasts (CAFs) have been associated with poorer patient outcomes. CAFs produce collagen and other pro-ECM factors that prevent anti-tumor T cells responses. Using an in vitro patient-derived osteosarcoma xenograft model system, the investigators demonstrated that their patented membrane-anchored and tumor-targeted IL-12-armed (attIL12) T cells successfully disrupted and/or eliminated high-density CAFs and ECM. They also found that treatment with the attIL12-T cells was inversely correlated with T-cell infiltration into the tumors. attIL12-T cell function was dependent on the engagement with cell-surface vimentin (CSV). Further examination found that attIL12-T cell treatment drove an elevation in interferon gammaproduction by CSV⁺ tumor cells and subsequent FAS-mediated apoptosis of CAFs. These data suggest that the addition of attIL12-T cells to current therapeutic treatment may improve survival rates of patients with osteosarcoma.

Plasma cell-free DNA hydroxymethylation profiling reveals anti-PD-1 treatment response and resistance biology in non-small cell lung cancer

Gulfem D Guler, Yuhong Ning, Ceyda Coruh, Giuliana P Mognol, Tierney Phillips, Maryam Nabiyouni, Kyle Hazen, Aaron Scott, Wayne Volkmuth, Samuel Levy
Journal for ImmunoTherapy of Cancer 2024;12:e008028 (11 January 2024)

RESEARCH

Summary:

Immune checkpoint inhibitors (ICIs) that target programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) have yielded durable anti-tumor responses in patients with non-small cell lung cancer (NSCLC), but only in a subset of patients. Recent studies have identified plasma cell-free DNA (cfDNA) 5-hydroxymethylation (5hmC) as liquid biopsy cancer detection but have not attempted to utilize this method to predict response to ICI treatment. Blood samples were collected from 31 patients with NSCLC prior to and throughout ICI therapy and analyzed for 5hmC-containing cfDNA. Within the first cycle of anti-PD-1 treatment there were changes observed in the plasma cfDNA 5hmC profiles of responding patients in immune-activation genes, compared to non-responders showing cfDNA 5hmC changes in epithelial to mesenchymal transition genes. These results show promise of a non-invasive method to predict responses to ICI treatments in patients with NSCLC.

PD-1 checkpoint inhibition enhances the antilymphoma activity of CD19-CAR-iNKT cells that retain their ability to prevent alloreactivity

Emmanuelle Moraes Ribeiro, Kathy-Ann Secker, Ana-Maria Nitulescu, Rebekka Schairer, Hildegard Keppeler, Anton Wesle, Hannes Schmid, Anita Schmitt, Brigitte Neuber, Daniela Chmiest, Silvia Podavini, Melanie Märklin, Boris Klimovich, Michael Schmitt, Fulya Korkmaz, Claudia Lengerke, Corina Schneidawind, Dominik Schneidawind
Journal for ImmunoTherapy of Cancer 2024;12:e007829 (31 January 2024)

RESEARCH

Summary:

The use of CD19-targeted chimeric antigen receptor (CAR) invariant natural killer (iNK) T cells has been shown to be effective for the treatment of malignancies and reduces relapse rates after transplantation. They have also been proven to prevent acute and chronic graft-versus-host disease (GVHD). However, due to prolonged engagement with their target cell, exhaustion is a problem for CD19-CAR-iNKT cells. The effect of adding the programmed death-1 checkpoint inhibitor nivolumab to CD19-CAR-iNKT cell treatment was analyzed in apoptosis and mixed lymphocyte reactions, and results showed that nivolumab reinvigorated the CD19-CAR-iNKT cells and increased their cytokine release, cytotoxicity, and survival without negatively affecting alloreactivity. In conclusion, the combination of CD19-CAR-iNKT cells with nivolumab can be a powerful cytotherapeutic option to prevent relapse and reducing the risk of GVHD after allogeneic stem cell transplant.

Peritumoral administration of immunomodulatory antibodies as a triple combination suppresses skin tumor growth without systemic toxicit

Quentin G Wright, Debottam Sinha, James W Wells, Ian H Frazer, Jazmina L Gonzalez Cruz, Graham Robert Leggatt
Journal for ImmunoTherapy of Cancer 2024;12:e007960 (31 January 2024)

RESEARCH

Summary:

Intravenous administration of immune checkpoint inhibitors (ICI) in skin cancers, while effective, has off-target toxicities. To determine whether peritumoral administration of ICIs was safer and more effective than intravenous administration, transplantable tumor models in mice were treated with an ICI cocktail via both routes. Analysis included the effects on the tumor microenvironment composition, tumor-specific CD8 T cells, and liver toxicity. Results showed that local administration of ICI therapy was more effective at a lower dose than intravenous therapy and had less toxicity. Additionally, local ICI treatment of primary tumors drove regression of distal untreated tumors and provided immune memory-mediated resistance to tumor re-challenge in a secondary location. These data indicate that peritumoral ICI treatment for skin tumors is advantageous in long-term efficacy and safety and suggest future trials should focus on peritumoral delivery of ICI therapy.

JITC is proud to welcome Michael T. Lotze, MD, as Incoming Editor-in-Chief. Following an extensive search by the Board of Directors of the Society for Immunotherapy of Cancer (SITC), Dr. Lotze was selected for this prestigious role, which he will transition into over the coming months.

Dr. Lotze received his MD from Northwestern University in 1974. After doing surgical training at the University of Rochester, he spent much of the following decade at the National Cancer Institute as Senior Investigator of the Surgery Branch. Dr. Lotze then became the founding Director and Chief of the Division of Surgical Oncology at the University of Pittsburgh, during which he developed their surgical oncology program. Over the years, Dr. Lotze also served in various capacities at pharmaceutical and biotechnology companies both large and small. He is currently Professor of Surgery, Immunology, and Bioengineering, Director of the Damage Associated Molecular Pattern Molecules (DAMP) Laboratories at UMPC Hillman Cancer Center and Senior Advisor to UPMC Enterprises.

His research includes the further identification of clinical biomarkers and surrogates in the setting of cancer, and modern immunotherapy and gene therapy, dendritic cell, T cell, and cytokine therapies, and investigation of the role of mitochondria, metabolism, and unscheduled cell death in cancer. Dr. Lotze has over 500 publications in peer reviewed journals and books, and previously served on the editorial boards of several journals.

An enthusiastic, long-time SITC member, Dr. Lotze has contributed greatly to the Society through various programs and initiatives, and in numerous roles, including SITC President 1998–2000. He was also honored with the society’s Visionary/Legacy Award in 2020 and the SITC Lifetime Achievement Award in 2021.

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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 35% discount on Article Processing Charges (APCs) for all JITC articles submitted and accepted through2024. This discount is applied post-acceptance, at which point a discount code is shared with the corresponding author.

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JITC also offers full waivers for the full 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 and editor/reviewer discounts, view the journal's APC policy. Additional questions may be directed to JITCEditor@sitcancer.org.