SITC 2021 round-up: does the new generation of Cell and Gene Therapies give us hope for tackling solid tumors?

The SmartAnalyst Oncology Team at EmerGENE sums up their key takeaways from the Society for Immunotherapy of Cancer (SITC) 2021 conference and explores the potential for cell and gene therapy (C&GT) advances to aid the fight against solid tumors.

SmartAnalyst, part of the EmerGENE network, is constantly monitoring the development in the C&GT arena, and we are committed to taking advantage of any occasion to network with other experts, sharing knowledge about new developments.

The SITC Conference 2021 presented such an opportunity, offering up plenty of interesting insight for us to explore. For us, the most interesting revelations were in the field of Chimeric Antigen Receptor T Cell (CAR-T) immunotherapy – particularly its ability to fight solid tumors in cancer patients.

Here are my key takeaways from what was discussed about the latest CAR-T developments:

Cytokines can enhance CAR-T efficacy

Cytokines play a crucial role in the initiation and maintenance of T-cell-mediated immune responses, which are usually downregulated in the tumor microenvironment (TME). Coexpression of immune modifying cytokines has been shown to improve cell viability, expansion, and potency.

It was interesting, therefore, to see that three studies presented at SITC demonstrated that cytokine armored CAR-Ts had better anti-tumor activity. Armored NKG2D CAR-T cells that included the IL-18 transgene showed prolonged sequential target cell killing compared to non-armored CAR-Ts. They also increased levels of interferon-gamma secretion upon antigen challenge (Celyad Oncology)^[1].

At high doses, some toxicity was seen in tumor-bearing models which were abrogated by systemic infusion of human IL-18 binding protein (IL-18BP).

De novo methylation of T-cell plasticity associated genes have a key part to play in tackling CAR-T cell exhaustion

Deletion of the de novo DNA methyltransferase 3 alpha (DNMT3A) in T cells expressing first- or second-generation CARs was shown at SITC to universally preserve the cells’ ability to proliferate and mount an antitumor response during prolonged tumor exposure.

Genome-wide DNA methylation profiling can define an atlas of genes targeted for epigenetic silencing including stem-associated genes, TCF7 and LEF13^[2], providing an exciting roadmap for potent CAR-T cell development.

Myeloids can also be harnessed to boost immune responses

A number of speakers at SITC explored the potential for myeloid cells to be used in tackling solid tumors. They explored myeloid cell biology, their role in immune suppression, and ways to engineer myeloid cells to use as therapeutics akin to adoptive T-cell therapies.

The premetastatic niche can be enriched in immune-suppressive genes in myeloid cell clusters. Using the syngeneic Rhabdomyosarcoma (RMS) mice model, research has shown that genetically engineered myeloid cells (GEMys) can be harnessed as a platform to deliver antitumor factor to reprogram metastatic microenvironment^[3].

The tip of the iceberg

Across EmerGENE we are continuously monitoring the landscape of C&GTs to provide better insights and solutions for our clients. Our proprietary C&GT datasets provide comprehensive coverage of clinical development of CAR-Ts, TCR T cell, NK cell and immune cell engagers in oncology. Armed with this information, our clients have the insight they need to develop more effective C&GTs that can transform the way we treat solid tumors in the future.

To find out more about the discoveries presented at SITC, read our Highlights from SITC 2021: Cell and Gene Therapy in Solid Tumors – Ray of Hope on the Horizon?

To learn how we can support your CAR-T innovation, contact us today: https://oneashfield.com/emergene-cell-gene-therapy/

References

^[1] E. Breman, A. S. Walravens, I. Gennart, et al. Armoring NKG2D CAR T cells with IL-18 improves in vivo anti-tumor activity [Abs#107]. In: SITC 2021; Nov 10-14; Washington DC. Available at: https://jitc.bmj.com/content/9/Suppl_2/A118.

^[2] B. Prinzing, C. C. Zebley, C. T. P. Fan, et al. Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Sci. Translational Med 2021;13(620). Available at: https://www.science.org/doi/10.1126/scitranslmed.abh0272.

^[3] S. Kaczanowska, D. Beury, H. Qin, et al. Genetically engineered myeloid cells (GEMys) as a platform to enhance antitumor immunity [Abs#209]. In: SITC 2021; Nov 10-14; Washington DC. Available at: https://jitc.bmj.com/content/9/Suppl_2/A220.