Blogs

Novel tri-specific T-cell engager targeting IL-13Rα2 and EGFRvIII provides long-term survival in heterogeneous GBM challenge and promotes antitumor cytotoxicity with patient immune cells

Daniel H Park, Pratik S Bhojnagarwala, Kevin Liaw, Devivasha Bordoloi, Nicholas J Tursi, Shushu Zhao, Zev A Binder, Donald O’Rourke, David B Weiner
Journal for ImmunoTherapy of Cancer 2024;12:e009604 (2 December 2024)
RESEARCH

Summary:

This study introduces a novel DNA-encoded tri-specific T cell engager (DTriTE) targeting glioblastoma multiforme (GBM), a highly lethal and antigenically heterogeneous brain cancer. The DTriTE, named DT2035, simultaneously targets two GBM-associated antigens, EGFRvIII and IL-13Rα2, while engaging T cells through CD3. In vitro, DT2035 demonstrated potent cytotoxic activity and cytokine release against antigen-expressing tumor cells. In vivo, it provided sustained tumor control and prolonged survival in mouse models of heterogeneous GBMs. RNA sequencing of T cells treated with DT2035 revealed enhanced T cell activation, proliferation, and cytotoxic pathways, including the upregulation of granzyme B and IFN-γ. DT2035 also activated patient-derived immune cells, achieving target-specific tumor cytotoxicity even in heavily pretreated individuals. Compared to monospecific therapies, DT2035 showed superior efficacy in addressing GBM’s antigenic diversity, reducing tumor escape. These findings highlight the potential of multivalent immunotherapies like DT2035 to overcome challenges in GBM treatment and warrant further clinical investigation.

Integrating binding affinity and tonic signaling enables a rational CAR design for augmented T cell function

Markus Barden, Patrick Ronan Elsenbroich, Vivian Haas, Moritz Ertelt, Philip Pervan, Lukas Velas, Bence Gergely, Árpád Szöőr, Dennis Christoph Harrer, Valerie Bezler, Astrid Holzinger, Rasmus Ulslev Wegener Friis, Gyorgy Vereb, Gerhard J Schütz, Clara T Schoeder, Andreas A Hombach, Hinrich Abken
Journal for ImmunoTherapy of Cancer 2024;12:e010208 (2 December 2024)
RESEARCH

Summary:

The efficacy of CAR T cell therapy in treating solid tumors has been limited due to early loss of functionality, inefficient tumor targeting, and poor persistence. This study addresses these challenges by designing CARs that integrate optimal antigen binding affinity with enhanced tonic signaling. Using a panel of anti-Her2 CARs with a wide range of affinities, the researchers established that both high-affinity binding and elevated antigen-independent tonic signaling are critical for sustained CAR T cell functionality. Their findings show that affinity above a threshold drives T cell activation, while increased tonic signaling, driven by scFv hydrophobic interactions, improves cell persistence and antitumor activity. CAR T cells with optimized signaling maintained functionality under repetitive antigen exposure and showed superior tumor control in mouse models. High-affinity CARs also exhibited robust clustering and signaling, even in the absence of antigen, enhancing their capacity for sustained expansion and long-term efficacy. This integrative approach provides insights into overcoming challenges in solid tumor treatment and highlights the need for a balance between antigen-triggered and tonic signaling in rational CAR design.

Natural lung-tropic TH9 cells: a sharp weapon for established lung metastases

Tao Chen, Chenxiao Qiao, Eloy Yinwang, Shengdong Wang, Xuehuan Wen, Yixuan Feng, Xiangang Jin, Shuming Li, Yucheng Xue, Hao Zhou, Wenkan Zhang, Xianchang Zeng, Zenan Wang, Hangxiang Sun, Lifeng Jiang, Hengyuan Li, Binghao Li, Zhijian Cai, Zhaoming Ye, Nong Lin
Journal for ImmunoTherapy of Cancer 2024;12:e009629 (4 December 2024)
RESEARCH

Summary:

Lung metastases remain a significant challenge in cancer treatment, often accompanied by poor patient outcomes. This study investigated the potential of T helper 9 (TH9) cells as a therapeutic strategy against established lung metastases. The authors demonstrated that TH9 cells are naturally attracted to the lungs, offering superior antitumor efficacy compared to other T helper subsets, including TH1 and TH17. Using murine models and adoptive cell transfer, findings suggested significant suppression of metastases and improved survival rates in mice transfused with TH9 cells. To understand underlying mechanisms, molecular/cellular assays, including flow cytometry and immunohistochemistry, were used to investigate chemokine receptor signaling. It was revealed that hyperactivation of NF-κB signaling in TH9 cells inhibits ITCH-mediated ubiquitination of the chemokine receptor CXCR4, leading to CXCR4 accumulation and enhanced lung tropism. In vivo imaging further confirmed the targeted migration of TH9 cells to metastatic sites in the lungs. These findings suggest that leveraging the natural lung-homing properties of TH9 cells could offer a promising immunotherapeutic approach for treating patients with established lung metastases.

Plasma arginine as a predictive biomarker for outcomes with immune checkpoint inhibition in metastatic colorectal cancer: a correlative analysis of the CCTG CO.26 trial

Lucy X Ma, Emma Titmuss, Jonathan M Loree, Derek J Jonker, Hagen F Kennecke, Scott Berry, Felix Couture, Chaudhary E Ahmad, John R Goffin, Petr Kavan, Mohammed Harb, Bruce Colwell, Setareh Samimi, Benoit Samson, Tahir Abbas, Nathalie Aucoin, Francine Aubin, Sheryl Koski, Dongsheng Tu, Christopher O’Callaghan, Eric X Chen
Journal for ImmunoTherapy of Cancer 2024;12:e010094 (4 December 2024)
RESEARCH

Summary:

APC Discounts

As a way to thank the SITC members who work tirelessly to advance the science and improve the lives of cancer patients, SITC members who are first, last, or corresponding authors on accepted JITC articles will receive discounted Article Processing Charges (APCs). This discount is applied post-acceptance, at which point a discount code is shared with the corresponding author. Learn more.

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.