Harvard: Potential Mechanism Driving Personalization of Cancer Immunotherapy

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Harvard: Potential Mechanism Driving Personalization of Cancer Immunotherapy

Another breakthrough in CAR-T cell therapy!

Harvard Research Team Uncovers Potential Mechanism Driving Personalization of Cancer Immunotherapy

Takeaway: New adaptive T-cell therapy, in which T cells, the immune system’s natural hunters, patrol the body for foreign adversaries, are retrieved from cancer-ridden patients, supercharged and expanded ex vivo, then infused into the same patient . This therapy is changing the landscape of cancer patient care.

Recently, the Harvard University research team published a paper “Enhancing CAR-T cell functionality in a patient-specific manner” in “Nature Communications”.

The study proved that personalized CAR-T cell stimulation during the production process can significantly improve the resulting CAR-T Consistency and potency of cellular products .

Harvard: Potential Mechanism Driving Personalization of Cancer Immunotherapy
https://www.nature.com/articles/s41467-023-36126-7

CAR-T cells

Since CAR-T cells (Chimeric Antigen Receptor) were approved by the US Federal Drug Administration (FDA) as the first modified therapeutic cell for leukemia in 2017, five similar products have been approved and more than 20,000 people were treated with this game-changing immunotherapy.

CAR-T cells are engineered to carry synthetic membrane-spanning receptor molecules that use their outward-facing parts to bind to antigens on cancer cells and their inward-facing parts to respond by switching on a powerful tumor cell destruction program . However, not all patients respond equally well to CAR-T cell therapy, and cancer immunologists have been trying to figure out what makes them work or fail.

Despite a burgeoning understanding of the differences between T cells from cancer patients and those from healthy individuals, these insights have not yet been taken into account during CAR-T cell manufacturing. All processes use similar types of stimulation with T cell-specific agonists and general immunostimulatory cytokines to generate a fusible CAR-T cell product regardless of changes in naive T cell phenotype.

Provide the key to personalized CAR-T therapy

The research team investigated the phenotypes of T cells they isolated from patients with acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), as well as samples obtained from healthy donors.

Next, they used APC-MS to stimulate T cells with different doses of anti-CD3/anti-CD28 antigens, thereby creating a CAR-T cell bank. All CAR-T cell products contained in the library were then again probed for functional differences, including their ability to kill cancer cells in vitro. The researchers directly compared their approach to an approach commonly used in CAR-T cell manufacturing, which presents T cells with the same antigen on rigid magnetic beads (Dynabeads).

A key finding was that T cells from cancer patients were more likely to be overstimulated than “healthy” T cells at antigen doses commonly used in CAR-T cell manufacturing . This makes them nonfunctional, or as immunologists call them, more “tired,” and reduces their ability to proliferate. CAR-T cells not only need to be converted to a functional state, but also expanded by millions to eliminate tumor cells and metastases throughout the body.

“By exploring the precise, narrow range of stimulating doses enabled by APC-MS, we show that there is a personalized ‘sweet spot’ for patient-derived T cells that maximizes function and expansion, ” said David Zhang. , on average, lower than usual doses. The APC-ms approach functions more naturally than Dynabeads because highly controllable levels of T cell signaling are embedded in the lipid bilayer, which allows CAR-T cells to push and pull them, just Like T cells that normally cross the ‘immune synapse’ between them and antigen-presenting cells when T-cell stimulation is at its best.”

From in vitro research to cell manufacturing

Although the team did not observe any significant differences between CAR-T cells created from ALL and CLL patient samples, overall, their method produced more cells with high cytotoxic potential for tumor cells, the cytotoxic A more balanced ratio between CD8 T cells and the CD4 T cells that support their function, as well as more memory T cells that are not themselves cytotoxic but can be activated in later responses.

In vivo studies in mice, infused CAR-T cell products generated with different levels of stimulation also showed markedly different abilities to control CD19-expressing Burkitt lymphoma, again at lower than usual levels during manufacture Stimulated cells showed the strongest potential.

” We built a proof-of-concept model based on quantifiable relationships between T cell blood sample phenotypes and their CAR-T cell products, and produced output for personalized CAR-T cells, ” said Wu, professor of medicine at Harvard Medical School. Optimal T cell stimulating dose. Given that T cell samples are always fingerprinted for important markers at the beginning of the cell manufacturing process, similar strategies can be devised to further personalize therapy using the APC-MS approach .”

References:

https://www.nature.com/articles/s41467-023-36126-7

Harvard: Potential Mechanism Driving Personalization of Cancer ImmunotherapyHarvard: Potential Mechanism Driving Personalization of Cancer Immunotherapy

(source:internet, reference only)

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