Baylor College of Medicine study: Fighting cancer with rejection-resistant, ‘off-the-shelf’ therapeutic T cells

21 Aug

William C. Shiel Jr., MD, FACP, FACR wrote in the Medicine Net article, Medical Definition of T cell:

T cell: A type of white blood cell that is of key importance to the immune system and is at the core of adaptive immunity, the system that tailors the body’s immune response to specific pathogens. The T cells are like soldiers who search out and destroy the targeted invaders.

Immature T cells (termed T-stem cells) migrate to the thymus gland in the neck, where they mature and differentiate into various types of mature T cells and become active in the immune system in response to a hormone called thymosin and other factors. T-cells that are potentially activated against the body’s own tissues are normally killed or changed (“down-regulated”) during this maturational process.

There are several different types of mature T cells. Not all of their functions are known. T cells can produce substances called cytokines such as the interleukins which further stimulate the immune response. T-cell activation is measured as a way to assess the health of patients with HIV/AIDS and less frequently in other disorders.

T cell are also known as T lymphocytes. The “T” stands for “thymus” — the organ in which these cells mature. As opposed to B cells which mature in the bone marrow.

https://www.medicinenet.com/script/main/art.asp?articlekey=11300

See,        https://drwilda.com/tag/cancer/

Regina Bailey wrote in the Thought Co. article, The Role of T Cells in the Body:

T cells are a type of white blood cell known as a lymphocyte. Lymphocytes protect the body against cancerous cells and cells that have become infected by pathogens, such as bacteria and viruses. T cell lymphocytes develop from stem cells in bone marrow. These immature T cells migrate to the thymus via the blood. The thymus is a lymphatic system gland that functions mainly to promote the development of mature T cells. In fact, the “T ” in T cell lymphocyte stands for thymus derived.

https://a4d45a61c2d866ec4a90d1a9315ab8ab.safeframe.googlesyndication.com/safeframe/1-0-37/html/container.html T cell lymphocytes are necessary for cell mediated immunity, which is an immune response that involves the activation of immune cells to fight infection. T cells function to actively destroy infected cells, as well as to signal other immune cells to participate in the immune response.

Key Takeaways: T Cells
  • T cells are lymphocyte immune cells that protect the body from pathogens and cancer cells.
  • T cells originate from bone marrow and mature in the thymus. They are important for cell mediated immunity and the activation of immune cells to fight infection.
  • Cytotoxic T cells actively destroy infected cells through the use of granule sacs that contain digestive enzymes.
  • Helper T cells activate cytotoxic T cells, macrophages, and stimulate antibody production by B cell lymphocytes.
  • Regulatory T cells suppress the actions of B and T cells to decrease the immune response when a highly active response is no longer warranted.
  • Natural Killer T cells distinguish infected or cancerous cells from normal body cells and attack cells that do not contain molecular markers that identify them as body cells.
  • Memory T cells protect against previously encountered antigens and may provide lifetime protection against some pathogens.
T Cell Types

T cells are one of three main types of lymphocytes. The other types include B cells and natural killer cells. T cell lymphocytes are different from B cells and natural killer cells in that they have a protein called a T-cell receptor that populates their cell membrane. T-cell receptors are capable of recognizing various types of specific antigens (substances that provoke an immune response). Unlike B cells, T cells do not utilize antibodies to fight germs.

There are several types of T cell lymphocytes, each with specific functions in the immune system. Common T cell types include:

  • https://a4d45a61c2d866ec4a90d1a9315ab8ab.safeframe.googlesyndication.com/safeframe/1-0-37/html/container.html Cytotoxic T cells (also called CD8+ T cells) – are involved in the direct destruction of cells that have become cancerous or are infected by a pathogen. Cytotoxic T cells contain granules (sacs containing digestive enzymes or other chemical substances) that they utilize to cause the target cell to burst open in a process called apoptosis. These T cells are also the cause of transplant organ rejection. The T cells attack the foreign organ tissue as the transplant organ is identified as infected tissue.
  • Helper T cells (also called CD4+ T cells) – precipitate the production of antibodies by B cells and also produce substances that activate cytotoxic T cells and white blood cells known as macrophages. CD4+ cells are targeted by HIV. HIV infects helper T cells and destroys them by triggering signals that result in T cell death.
  • Regulatory T cells (also called suppressor T cells) – suppress the response of B cells and other T cells to antigens. This suppression is needed so that an immune response does not continue once it is no longer needed. Defects in regulatory T cells can lead to the development of an autoimmune disease. In this type of disease, immune cells attack the body’s own tissue.
  • https://a4d45a61c2d866ec4a90d1a9315ab8ab.safeframe.googlesyndication.com/safeframe/1-0-37/html/container.html Natural Killer T (NKT) cells – have a similar name as a different type of lymphocyte called a natural killer cell. NKT cells are T cells and not natural killer cells. NKT cells have properties of both T cells and natural killer cells. Like all T cells, NKT cells have T-cell receptors. However, NKT cells also share several surface cell markers in common with natural killer cells. As such, NKT cells distinguish infected or cancerous cells from normal body cells and attack cells that do not contain molecular markers that identify them as body cells. One type of NKT cell known as an invariant natural killer T (iNKT) cell, protects the body against obesity by regulating inflammation in adipose tissue.
  • Memory T cells – help the immune system to recognize previously encountered antigens and respond to them more quickly and for a longer period of time. Helper T cells and cytotoxic T cells can become memory T cells. Memory T cells are stored in the lymph nodes and spleen and may provide lifetime protection against a specific antigen in some cases.

https://tpc.googlesyndication.com/safeframe/1-0-37/html/container.html https://www.thoughtco.com/t-cells-meaning-373354

Bailey, Regina. “The Role of T Cells in the Body.” ThoughtCo, Feb. 11, 2020, thoughtco.com/t-cells-meaning-373354.              

Science Daily reported in Fighting cancer with rejection-resistant, ‘off-the-shelf’ therapeutic T cells:

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

Cancer patients today can be a part of the following clinical scenario: a patient comes to the hospital where physicians and scientists analyze his or her tumor to identify cancer-specific markers that would serve as targets for the novel 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 infused back into the patient to complete their job.

“At the Center, we genetically engineer 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 Dr. 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 trained T cells are not highly potent because the patient already received a number of treatments that weakened the immune cells we work with,” Mamonkin said.

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

The next step: off-the-shelf therapies

“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 make sure that the resulting T cells have the highest potency,” said Mamonkin, who also is a member of the Dan L Duncan Comprehensive Cancer Center.

Researchers are developing ready-to-use, off-the-shelf therapeutic T cells. These are genetically engineered T cells that are manufactured from normal, healthy donors. The cells are expanded and well characterized, and have shown to be effective at killing cancer cells. The cells are cryo-preserved — stored frozen in liquid nitrogen — until it’s 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 physician goes to a room filled with large below-zero freezers searching for the one that holds little containers with healthy immune T cells that have been genetically engineered to recognize and destroy cells with the patient’s cancer-specific markers. These ‘off-the-shelf,’ ready-made cells are thawed, prepared and infused into the patient several days later….    https://www.sciencedaily.com/releases/2020/08/200820143825.htm

Citation:

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

Date:         August 20, 2020

Source:     Baylor College of Medicine

Summary:

Researchers are developing ready-to-use, off-the-shelf therapeutic T cells. These are genetically engineered T cells that are manufactured from normal, healthy donors. The cells are expanded and well characterized, and have shown to be effective at killing cancer cells.

Journal Reference:

Feiyan Mo, Norihiro Watanabe, Mary K. McKenna, M. John Hicks, Madhuwanti Srinivasan, Diogo Gomes-Silva, Erden Atilla, Tyler Smith, Pinar Ataca Atilla, Royce Ma, David Quach, Helen E. Heslop, Malcolm K. Brenner, Maksim Mamonkin. Engineered off-the-shelf therapeutic T cells resist host immune rejectionNature Biotechnology, 2020; DOI: 10.1038/s41587-020-0601-5

Here is the press report from Baylor College of Medicine:

NEWS RELEASE 

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

BAYLOR COLLEGE OF MEDICINE

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

Cancer patients today can be a part of the following clinical scenario: a patient comes to the hospital where physicians and scientists analyze his or her tumor to identify cancer-specific markers that would serve as targets for the novel 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 infused back into the patient to complete their job.

“At the Center, we genetically engineer 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 Dr. 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 trained T cells are not highly potent because the patient already received a number of treatments that weakened the immune cells we work with,” Mamonkin said.

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

The next step: off-the-shelf therapies

“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 make sure that the resulting T cells have the highest potency,” said Mamonkin, who also is a member of the Dan L Duncan Comprehensive Cancer Center.

Researchers are developing ready-to-use, off-the-shelf therapeutic T cells. These are genetically engineered T cells that are manufactured from normal, healthy donors. The cells are expanded and well characterized, and have shown to be effective at killing cancer cells. The cells are cryo-preserved – stored frozen in liquid nitrogen – until it’s 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 physician goes to a room filled with large below-zero freezers searching for the one that holds little containers with healthy immune T cells that have been genetically engineered to recognize and destroy cells with the patient’s cancer-specific markers. These ‘off-the-shelf,’ ready-made cells are thawed, prepared and infused into the patient several days later.

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

Dealing with rejection

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

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

“Both experiments in the lab and animal models with blood cancers or solid tumors showed that ADR protected off-the-shelf therapeutic T cells from being rejected,” Mo said. “Not only did they resist rejection, but they also expanded more and persisted 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 on 2021.

Beyond cancer applications

“If successful, this approach can be extended to targeting other disease-causing T-cells, such as those rejecting transplanted organs, mediating graft-versus-host disease or perpetuating autoimmunity,” said Mamonkin. “We are very excited to develop this concept for several applications beyond cancer therapy.” This technology has been licensed to Fate Therapeutics, a clinical-stage biopharmaceutical company that plans on integrating ADR into their clinical products.

“The BCM Ventures team is very pleased to partner 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 to enhance the effectiveness of off-the-shelf cell therapies, and it will now be used more extensively in the clinical setting which stands to 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 increasingly looks to BCM as a source for new innovations.”

Feiyan Mo, who took the lead on this work, has received an NIH NCI F99/F00 Predoctoral-to-postdoctoral Fellowship Award to help facilitate the translation of ADR to the clinic and continue postdoctoral studies in cancer biology. She is a Baylor graduate student and is co-mentored by Drs. Mamonkin, Malcolm Brenner and Helen Heslop. Are you interested in learning all the details of this work? Find them in the journal Nature Biotechnology.

###

Other contributors of this study include Feiyan Mo, Norihiro Watanabe, Mary K. McKenna, M. John Hicks, Madhuwanti Srinivasan, Diogo Gomes-Silva, Erden Atilla, Tyler Smith, Pinar Ataca Atilla, Royce Ma, David Quach, Helen E. Heslop and Malcolm K. Brenner. The authors are affiliated with one of more of the following institutions Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital.

This project was supported by the Leukemia and Lymphoma Society Translational Research Award no. 6566, NIH NCI SPORE in Lymphoma 5P50CA126752, SU2C/AACR 604817 Meg Vosburg T cell Lymphoma Dream Team, Gloria Levin Fund and CPRIT Award nos. RP180810 and RP150611. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. The Dan L Duncan Comprehensive Cancer Center also provided support through its shared resources (P30 CA125123).

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

The National Cancer Institute wrote in How does T-cell transfer therapy work against cancer?

T-cell transfer therapy is a type of immunotherapy that makes your own immune cells better able to attack cancer. There are two main types of T-cell transfer therapy: tumor-infiltrating lymphocytes (or TIL) therapy and CAR T-cell therapy. Both involve collecting your own immune cells, growing large numbers of these cells in the lab, and then giving the cells back to you through a needle in your vein. T-cell transfer therapy is also called adoptive cell therapy, adoptive immunotherapy, and immune cell therapy.

The process of growing your T cells in the lab can take 2 to 8 weeks. During this time, you may have treatment with chemotherapy and, maybe, radiation therapy to get rid of other immune cells. Reducing your immune cells helps the transferred T cells to be more effective. After these treatments, the T cells that were grown in the lab will be given back to you via a needle in your vein.

  • TIL therapy uses T cells called tumor-infiltrating lymphocytes that are found in your tumor. Doctors test these lymphocytes in the lab to find out which ones best recognize your tumor cells. Then, these selected lymphocytes are treated with substances that make them grow to large numbers quickly.

The idea behind this approach is that the lymphocytes that are in or near the tumor have already shown the ability to recognize your tumor cells. But there may not be enough of them to kill the tumor or to overcome the signals that the tumor is releasing to suppress the immune system. Giving you large numbers of the lymphocytes that react best with the tumor can help to overcome these barriers.

  • CAR T-cell therapy is similar to TIL therapy, but your T cells are changed in the lab so that they make a type of protein known as CAR before they are grown and given back to you. CAR stands for chimeric antigen receptor. CARs are designed to allow the T cells to attach to specific proteins on the surface of the cancer cells, improving their ability to attack the cancer cells.

What cancers are treated with T-cell transfer therapy?

T-cell transfer therapy was first studied for the treatment of metastatic melanoma because melanomas often cause a strong immune response and often have many TILs. The use of TIL therapy has been effective for some people with melanoma and has produced promising findings in other cancers, such as cervical squamous cell carcinoma and cholangiocarcinoma. However, this treatment is still experimental.

Two CAR T-cell therapies have been approved by the Food and Drug Administration, both for blood cancers:

CAR T-cell therapy has also been studied for the treatment of solid tumors, including breast and brain cancers, but use in such cancers is still experimental.

What are the side effects of T-cell transfer therapy?

T-cell transfer therapy can cause side effects, which people experience in different ways. The side effects you may have and how serious they are will depend on how healthy you are before treatment, your type of cancer, how advanced it is, the type of T-cell transfer therapy you are receiving, and the dose.

Doctors and nurses cannot know for sure when or if side effects will occur or how they will affect you. So, it is important to know which signs to look for and what to do if you start to have problems.

CAR T-cell therapy can cause a serious side effect known as cytokine release syndrome. This syndrome is caused when the transferred T cells, or other immune cells responding to the new T cells, release a large amount of cytokines into the blood.

Cytokines are immune substances that have many different functions in the body. A sudden increase in their levels can cause:

  • Fever
  • Nausea
  • Headache
  • Rash
  • Rapid heartbeat
  • Low blood pressure
  • Trouble breathing

Most patients have a mild form of cytokine release syndrome, but in some people it may be severe or life threatening.

Also, although CAR T cells are designed to recognize proteins that are found only on cancer cells, they can also sometimes recognize normal cells. Depending on which normal cells are recognized, this can cause a range of side effects, including organ damage.

TIL therapy can cause capillary leak syndrome. This syndrome causes fluid and proteins to leak out of tiny blood vessels and flow into surrounding tissues, resulting in dangerously low blood pressure. Capillary leak syndrome may lead to multiple organ failure and shock.

For more information about CAR T-cell therapy see CAR T-Cell Therapy: Engineering Patients’ Immune Cells to Treat Their Cancers.

https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/t-cell-transfer-therapy

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