T-cell therapy for all tumors

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T-cell therapy is a promising approach for the treatment of various types of cancers, including solid tumors. T-cells are a type of immune cell that can recognize and kill cancer cells, but they often need to be activated and targeted specifically to the tumor cells.

There are different types of T-cell therapies for cancer, including CAR-T cell therapy and TCR-T cell therapy. CAR-T cell therapy involves modifying a patient’s own T-cells in the laboratory to express chimeric antigen receptors (CARs) that recognize and bind to specific tumor antigens. The modified T-cells are then infused back into the patient’s body to target and kill the cancer cells.

TCR-T cell therapy involves modifying a patient’s T-cells to express T-cell receptors (TCRs) that recognize specific tumor antigens. This approach can target a broader range of tumor antigens than CAR-T cell therapy.

TCRs are proteins on the surface of T-cells that can recognize and bind to specific antigens, which are molecules on the surface of cells that can elicit an immune response. By modifying a patient’s T-cells to express TCRs that recognize tumor antigens, the modified T-cells can target and kill cancer cells.

Unlike CAR-T cell therapy, which uses chimeric antigen receptors (CARs) that recognize antigens independent of the major histocompatibility complex (MHC), TCR-T cell therapy requires recognition of tumor antigens that are presented by MHC molecules on the surface of cancer cells. This means that TCR-T cell therapy can target a wider range of tumor antigens, including those that are not well-defined or not expressed on the surface of cancer cells.

However, TCR-T cell therapy also has its own challenges, including the need to identify suitable tumor antigens and to overcome immune evasion mechanisms used by cancer cells. Nevertheless, TCR-T cell therapy has shown promising results in early clinical trials for some types of cancers, such as melanoma and synovial sarcoma.

T-cell therapy for all tumors

Instead of delivering antibodies, another type of immunotherapy called adoptive T-cell therapies involves extracting T cells from patients, engineering them to target the patient’s particular form of cancer, and delivering them back into the blood to enhance the immune response.

These therapies are remarkably effective against blood cancers, but so far have shown limited success against solid tumors. A team in the lab of Core Faculty member Dave Mooney, Ph.D., has developed a technique that allows them to metabolically “tag” the surface of T cells with cytokines, which enhance the anti-tumor activity of immune cells.

This technique avoids the negative side effects that prevent cytokines from being delivered systemically, and effectively treated both solid and liquid tumors in mice as an add-on to CAR-T cell therapy. This technology could boost the efficacy of multiple forms of cellular therapies, and is currently being de-risked.

“Waking up” deactivated macrophages

T cells aren’t the only immune cells involved in fighting off invaders – macrophages, or white blood cells, constantly patrol the body for threats, and are often the first cells to flock to a tumor.

However, tumors secrete molecules that deactivate macrophages upon arrival, to the point that as much as 50% of a tumor’s mass is made of macrophages.

A Wyss team led by Core Faculty member Samir Mitragotri, Ph.D., is solving this problem by attaching tiny “backpacks” – disc-shaped nanoparticles loaded with proinflammatory cytokines – to macrophages.

When infused into the body, these macrophages can switch those inside a tumor from an “off” state to an “on” state, reactivating them against the cancer.

The team is now investigating this technology for use in treating glioblastoma, as macrophages are able to penetrate the infamously tough blood-brain barrier that prevents most drugs from reaching the brain.

The backpacks’ disk shape (purple) allows them to attach to macrophages (white) without being engulfed and digested, helping to prolong the effects of their cargo. Credit: Wyss Institute at Harvard University.

Deliberately designing vaccines with DNA

Although immunotherapies are a relatively new technology, a much older technique also works by stimulating the body’s immune response: vaccines. Many labs and companies are developing personalized cancer vaccines that preemptively train the immune system to recognize and kill cancer,

These vaccines typically contain an antigen (a protein fragment taken from a patient’s cancer cells that activates antigenpresenting cells [APCs]) and an adjuvant (a molecule that enhances the immunestimulating response of APCs).

Both an antigen and an adjuvant are required for an effective tumor-specific response, but little is known about the optimal method of presenting these components to APCs. Core Faculty member William Shih, Ph.D., and his lab have created a solution composed of the stuff of life itself: DNA.

Their DoriVac technology consists of folded sheets of DNA origami whose configuration can be controlled down to the nanoscale. This precision has allowed them to experiment with different arrangements of antigens and adjuvants in cancer vaccines, and they have identified patterns that produced strong tumorinhibiting responses in mice and could be combined with other cancer treatments for better outcomes. The team is de-risking their innovation for commercialization.

DoriVac is a novel technology for cancer immunotherapy that is currently being developed by the biotechnology company, Hookipa Pharma Inc. DoriVac is based on a virus vector platform that can deliver tumor-specific antigens to dendritic cells, a type of immune cell that can activate T-cells and initiate an immune response against cancer cells.

In DoriVac, a virus vector is engineered to express tumor-specific antigens, which are then presented to dendritic cells. This presentation of tumor-specific antigens by dendritic cells can activate T-cells that can specifically target and kill cancer cells that express the same tumor-specific antigens. The use of dendritic cells in this process is important, as they are known to be very effective in activating T-cell responses against cancer cells.

One of the potential advantages of DoriVac over other immunotherapies is that it can target multiple tumor-specific antigens simultaneously, potentially increasing its effectiveness in treating different types of cancers. Additionally, DoriVac is designed to be administered as a single injection, which could improve patient convenience and compliance.

DoriVac is still in the preclinical development stage, and further studies are needed to assess its safety and effectiveness in humans. Nevertheless, the technology has shown promising results in animal studies, and it is being developed for potential use in a range of cancers, including lung cancer, melanoma, and cervical cancer.

reference link :https://wyss.harvard.edu/news/immunotherapys-next-act/

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