Posted November 17, 2023

Jared Weiss, M.D., and Barbara Savoldo, M.D., Ph.D., University of North Carolina at Chapel Hill

Cancer can be viewed as a failure of the immune system and many modern therapeutics aim to treat, or even cure metastatic cancer by helping the body’s own immune system. Most of the FDA approved medications work by helping a particular kind of immune cell, called T cells. T cells are very powerful, but they can only work under very specific conditions.

Healthy cells as well as most cancer cells resulting from them play “show and tell” with the immune system. They present copies of proteins that they make on their cell surface. The body has a library of T cells, each of which can recognize one particular foreign protein presented by one particular holder, called “human leukocyte antigen” or “HLA.”

T cells have certain weaknesses. Cancer cells can hide from the immune system by expression of other molecules called “checkpoints.” They can also stop expressing the HLA type that presents the foreign protein that a T cell recognizes. For these reasons, immunotherapies that rely on these classical mechanisms fail more often than they succeed, and resistance can emerge.

Another approach is to attack foreign elements present on the surface of the cancer cell itself (without HLA presentation). In the unmodified immune system, such elements can be recognized by antibodies, but antibodies are far less potent against cancer than T cells and therefor have only modest activity.

Chimeric antigen receptor, or CAR, T cells are genetically modified to use an antibody’s sequence to “hang off’ the T cell and activate it when it binds the specific cell surface target. This marries the surface recognition of antibodies with the killing power of T cells. The FDA approved the use of six CAR T cells as treatment for certain types of leukemia, lymphoma, and myeloma.¹ Investigators are seeking ways to improve this CAR T approach and adapt its use for the treatment of other cancers, including lung cancer.²

With support from a fiscal year 2021 Lung Cancer Research Program Clinical Translational Research Partnership Award, Dr. Jared Weiss and Dr. Barbara Savoldo aim to conduct a phase 1 dose escalation clinical trial to evaluate the safety and effectiveness of an innovative CAR T construct, iC9.GD2.CAR.IL15, in participants with incurable small cell lung cancer (SCLC) and stage IV non-small cell lung cancer (NSCLC).

Dr. Weiss and Dr. Savoldo’s team brought developments from their other studies to the research for this award. Through their previous research, they developed CAR T cells targeting the GD2 disialoganglioside, a protein the team found to be overexpressed on cells of both SCLC and NSCLC.³ This CAR T contains two innovative, unique features in the construct: (1) contains interleukin 15 (IL15), a cytokine that induces amplification of the CAR T population, and (2) incorporates an inducible safety switch caspase 9 (iC9), a molecular safety feature to inactivate the CAR T cells if a patient is experiencing adverse treatment effects. Previous data show the effectiveness of iC9.GD2.CAR.IL15 T cells on SCLC and NSCLC cell lines and in mouse models of human lung tumors.³

This phase 1 clinical trial is designed to evaluate the safety of escalating doses of iC9.GD2.CAR.IL15 T cells. The research team will monitor participant responses, including symptoms of cytokine release syndrome, an adverse reaction that occurs due to over activation of the immune system resulting from T cell stimulation.⁴ Through blood analyses and biopsies, the team aims to characterize iC9.GD2.CAR.IL15 T cells in circulation and in tumor samples to determine how these CAR T cells affect the tumor microenvironment and correlate with disease progression or response. In a series of laboratory experiments, the team will expose SCLC and NSCLC cell lines to drugs that modulate chromatin (bundled DNA and protein), with the goal of increasing GD2 expression, thereby enhancing the ability of iC9.GD2.CAR.IL15 T cells to target tumors. Dr. Weiss and Dr. Savoldo will further test promising compounds to evaluate the degree to which their activity enhances iC9.GD2.CAR.IL15 T cells potency, meaning the potential to slow or inhibit the cancer progression.

The iC9.GD2.CAR.IL15 construct was already being tested in clinical trials for the treatment of neuroblastoma and osteosarcoma, other cancers that express GD2⁵ and the phase I study in lung cancer has already started. Because GD2 is overexpressed on a variety of lung cancers (squamous non-small cell, adenocarcinoma non-small cell and small cell) patients with all of these tumor types are eligible. The innovative IL15 self-amplification component and iC9 kill switch are intended to improve the proliferation and safety of iC9.GD2.CAR.IL15, respectively. If effective, iC9.GD2.CAR.IL15 may offer patients a new immunotherapeutic option independent of HLA presentation, thus broadly applicable.

References:

1. CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
2. Chen Y, Sun C, Landoni E, et al. 2019. Eradication of Neuroblastoma by T cells Redirected with an Optimized GD2-Specific Chimeric Antigen Receptor and Interleukin- 15. Clin Cancer Res 25(9):2915. https://doi.org/10.1158/1078-0432.CCR-18-1811
3. Reppel L, Tsahouridis O, Akulian J, et al. 2022. Targeting disialoganglioside GD2 with chimeric antigen receptor-redirected T cells in lung cancer. Journal for Immunotherapy of Cancer 10(1):e003897. https://doi.org/10.1136/jitc-2021-003897
4. Study of CAR T-Cells Targeting the GD2 With IL-15+iCaspase9 for Relapsed/Refractory Neuroblastoma or Relapsed/Refractory Osteosarcoma. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT03721068
5. Autologous CAR T-Cells Targeting the GD2 Antigen for Lung Cancer. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05620342

Links:
Public and Technical Abstracts: GD2 CART for Lung Cancer

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Last updated Thursday, November 16, 2023