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Enhanced Cell Immunotherapy Approach Using Multi-Specific Cytotoxic CD4+ T Cells

A new technique from Dana-Farber scientists rapidly generates CD4+ cytotoxic T lymphocytes against multiple tumor antigens and can be used as an adoptive cell therapy for multiple cancers, including B-cell malignancies as well as solid tumors.

Therapeutics

Project Overview

Research has shown cancer patients with high levels of tumor-specific CD4+ T cells have better overall survival following CAR T treatment.
Dana‑Farber’s approach to improving CD4+ cell therapies includes generating CD4+ cytotoxic T lymphocytes (CTLs) that can quickly target multiple tumor antigens.
CD4+ CTLs are superior at in vivo persistence providing long-lasting antitumor immunity.
Dana-Farber’s CD4+ CTL technique is available for sponsored research or licensing.

Technology

Cell therapy for cancer, also known as cellular immunotherapy or adoptive cell transfer (ACT), has shown remarkable success in some cases, mainly in B-cell malignancies. In these cases, treatment leads to complete remission and long-term survival in patients who have limited treatment options. A key example of cell therapy is CAR T-cell therapy which involves modifying a patient’s own T cells to target and destroy cancer cells.

A major obstacle with cell therapy is that some approaches can be limited by the paucity of targetable antigens, allowing cancer variants without the target antigens to escape detection. In addition, some cancers have developed other immune evasion mechanisms. Therefore, there is a significant need to identify better methods to prime T cells against a broad spectrum of tumor antigens.

Traditionally, CD8+ CTLs have been considered the primary effector cells in tumor elimination, as they directly recognize and kill cancer cells. CD4+ CTLs (Cytotoxic T lymphocytes) are a specific subset of immune cells that can play a crucial role in cancer immunotherapy. Recent research has highlighted the importance of CD4+ CTLs in enhancing the anti-tumor immune response and in direct cancer-killing. Study data show that the presence of tumor-specific CD4+ T cells is associated with improved clinical outcomes and long-term survival in patients receiving CAR T-cell therapy.

Baochun Zhang, MD, PhD, of the Department of Medical Oncology and Department of Cancer Immunology and Virology at Dana-Farber, has developed a unique approach to generating these powerful effector CD4+ CTLs by harnessing the biology of the Epstein-Barr virus (EBV).

EBV is a ubiquitous virus that infects human B cells and epithelial cells and has tumorigenic potential. T cells eradicate EBV-infected cells, but afterward, the virus acquires a dormant state in a small number of B cells, establishing a lifelong latent infection in ~95% of humans. EBV is under constant immune surveillance but can spread from these cells during immunosuppression, resulting in an expansion of infected B cells and transformation into cancers, including lymphomas.

EBV’s malignant transformation of B cells is partially dependent on the expression of the latent membrane protein 1 (LMP1), a viral oncogene encoded by EBV. LMP1, however, has a dual role: it promotes transformation to cancers like lymphomas, and LMP1 triggers potent immune surveillance of EBV-infected B cells in vivo. It does so by inducing the expression and presentation of tumor-associated antigens (TAAs) along with the upregulation of costimulatory ligands CD70 and OX40L. Ultimately, this cascade of events induces cytotoxic CD4 T cell (CD4 CTL) and CD8 T cell responses, representing a novel mechanism of infection-induced anti-tumor immunity.

As described in a 2021 Nature paper, the Zhang lab developed a novel method for quickly and simply generating powerful CD4+ CTLs that hijacks the unique immunostimulatory function of LMP1 in order to generate multiclonal CD4 CTLs for treating B-cell malignancies. These CTLs exhibit T-cell receptors (TCRs) against multiple tumor antigens, including TAAs as well as neoantigens, new proteins that form only on cancer cells following DNA mutations.

Furthermore, to make CD4 CTL therapy available for a broader range of cancers beyond B-cell malignancies, such as solid cancers, the Zhang lab developed a second non-LMP1 based approach for generating CD4 CTLs. The generation of a wide diversity of T-cell receptors against multiple tumor antigens means that there is no need for antigen identification and they can be combined with immune checkpoint blockade therapies.

This approach overcomes the limitations of current ACT therapies targeting single TAAs, which show limited efficacy, make it easy for tumor immune escape, and often result in autoimmune toxicity. It may also offer an alternative immunotherapy approach to CAR T-cell therapies since the in vivo persistence of CAR T-cells remains limiting.

The American Cancer Society, Leukemia & Lymphoma Society, and Cancer Research Institute have provided funding for the project.

Team Members: Baochun Zhang, MD, PhD, Jerome Ritz, MD, Jutatip Panaampon, PhD, Jiankun Guan, PhD, Jiankun Guan, PhD, Zhe Wang, PhD, Il-Kyu Choi, PhD

Applications

The technology provides the means to generate CD4+ T cells against multiple tumor antigens in a simple and quick way for cancer cell therapy. This technology can be applied in the form of ACT, fulfilling an urgent need for developing a method targeting a large repertoire of tumor antigens.

CD4 CTLs may have great potential in treating B-cell lymphomas/leukemias and could also be applied to other cancers, such as melanoma, breast cancer, and bladder cancer, and those that otherwise escape CD8+ T cell-mediated killing.

Interested in learning more?

New cell therapy platform: Multi-specific cytotoxic CD4+ cells

INPART technology summary

Mechanism of EBV inducing anti-tumour immunity and its therapeutic use

Nature paper

Opportunities

Dana-Farber is interested in partnering with organizations for sponsored research and for licensing the technology to companies to develop new immunotherapies.

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