Fight cancer with rejection-resistant, ‘off-the-shelf’ therapeutic T cells

Personalized cancer treatments are no longer just options of the future. In recent years, researchers have made significant advances in ‘learning’ the body’s immune T cells to recognize and kill specific cancer cells, and human clinical studies have shown that this approach can successfully eliminate tumors.

Cancer patients today may be part of the following clinical scenario: A patient comes to the hospital where doctors and scientists analyze his or her tumor to identify cancer-specific markers that would serve as targets for the new therapy. Blood is drawn from the patient and sent to Baylor College of Medicine’s Center for Cell and Gene Therapy, where the immune T cells are transformed into cells with a mission to identify and kill cells with the tumor-specific tags. The final cells are returned to the patient to complete their orbit.

“At the center, we manipulate the patient’s T cells to arm them with the tools they need to identify the patient’s tumor – specific markers and eliminate the cancer,” said Drs. Maksim Mamonkin, Assistant Professor of Pathology & Immunology and Member of the Center for Cell and Gene Therapy at Baylor.

Although this treatment can effectively eliminate tumors, the ‘training’ of the T cells is complex and expensive. “Sometimes the charged T cells are not very potential because the patient has already received a number of treatments that weaken the immune cells with whom we work,” Mamonkin said.

In addition, the process of producing the therapeutic T cells is time consuming. “Sometimes it takes weeks to get the T cells ready, and during this time the patient can take a turn for the worse,” Mamonkin said.

The next step: Therapies that do not contain

“Now that we know that this type of cell immunotherapy has a lot of promise, the next step is to streamline it, make it more accessible and ensure that the resulting T cells have the highest potency,” said Mamonkin, who also a member of the Dan L Duncan Comprehensive Cancer Center.

Researchers are developing clear, off-the-shelf therapeutic T cells. These are genetically engineered T cells that are produced by normal, healthy donors. The cells are extensive and well characterized, and have been shown to be effective in cancer cells. The cells remain cryo-stored – stored frozen in liquid nitrogen – until it is time to use them. In this scenario, a cancer patient comes to the hospital and the tumor markers are identified. Then, with the identity of the tumor-specific tags in hand, the doctor goes to a room full of large freezers below zero in search of the one containing small containers with healthy immune T cells that are genetically made to recognize and destroy cells with the patient’s cancer – specific markers. These ‘off-the-shelf’, prepared cells are discovered, prepared and infused into the patient several days later.

“This approach solves two limitations of the original approach: it prevents the time-consuming, elaborate steps of training and expanding the patient’s cells and results in higher potential therapeutic T cells,” Mamonkin said. “However, the new approach presents a new set of limitations.”

Dealing with rejection

One of the limitations of the off-the-shelf approach appears when the therapeutic T cells enter the patient’s body. The patient’s own immune system recognizes the cells as foreign, as happens with organ transplants, and can reject the therapeutic cells.

“This is a big problem, because rejection would not only reduce the duration of T cell activity against the tumor, but would also prevent subsequent doses of cells from giving up. The immune system would produce successive doses of ‘ reject the cells in the right way, “said first author, Feiyan Mo, a graduate student in Mamonkin’s lab. “To solve this problem, we thought the best defense was a good crime.” The researchers gave the therapeutic T cells a tool that could activate them to fight the attack of the patient’s immune cells against them. They have genetically engineered the therapeutic T cells to express a prescription called the alloimmune defense receptor, or ADR. ADR recognizes a specific molecule, called 4-1BB, that is expressed only on the activated T cells of the patient and natural killer (NK) cells that would attack them. 4-1BB is not expressed on resting T and NK cells that do not rotate against the therapeutic T cells.

“Both laboratory experiments and animal models with blood cancer as well as solid tumors showed that ADR-protected therapeutic T cells are rejected from the shelves,” said Mo. “Not only does it resist rejection, but it also expands more and persists longer than therapeutic T cells without ADR.” The researchers are optimistic that this approach may also work in patients. They plan to conduct clinical trials by 2021.

Beyond cancer applications

“If successful, this approach could be extended to target other disease-causing T cells, such as those that reject transplant organs, meditate on graft-versus-host disease, or maintain autoimmunity,” Mamonkin said. “We are very excited to develop this concept for various applications outside of cancer therapy.” This technology is licensed to Fate Therapeutics, a clinical-stage bio-pharmaceutical company that plans to integrate ADR into its clinical products.

“The BCM Ventures team is very pleased to work with Fate Therapeutics in a licensing relationship to support their implementation of the ADR technology developed in the Mamonkin laboratory here at BCM. This approach promises the effectiveness of therapies for off- improve the shelf, and it will now be used more extensively in the clinical setting that can benefit patients, ”said Michael Dilling, director of Baylor Licensing Group. “BCM has been an innovator in the development of cell therapies and the commercial sector is increasingly looking to BCM as a source for new innovations.”