As an important part of the adaptive immune system, T cells play an essential role in the natural surveillance of and the fight against cancer. Over the last decades, the scientific community has started using T cells as a versatile tool for the development of cancer therapies. One example is the use of tumor-infiltrating lymphocytes (TILs), which are extracted from the tumor, selected and amplified and finally reintroduced into the patient to fight the cancer.
In the last two decades, however, the use of T cells in cancer therapy has seen a shift. “The concept of the natural potency of T cells can now be combined with our engineering capabilities, which have greatly advanced,” says Adi Barzel, Principal Investigator, President of the Israeli Society of Gene and Cell Therapy and ICLE Conference Chair. “We can now endow T cells with desired specificities by introducing genes into the genome of these T cells that code for receptors of choice, which in turn, can interact and detect cancer antigens.”
T cell receptors and CAR-T therapy
The receptors of choice Barzel refers to are T cell receptors (TCR) – similar to those naturally found on T cells – and chimeric antigen receptors (CAR), engineered moieties that comprise several different parts, each of which plays an important role in the immune response against cancer. While the antibody-like outer cellular part of CARs engages with the cancer cell, the intracellular parts are signal transduction domains that come from T cells. When the antibody-like domain engages with the cancer antigen, the signaling domain activates the T cells, triggering the attack.
Both TCRs and CARS are now in clinical use. Whereas engineered TCRs are still in the clinical trial stage, two CAR-T therapies have already been approved by the FDA. Novartis’ tisagenlecleucel (KymriahⓇ) was approved in August 2017 for the treatment of acute lymphoblastic leukemia (ALL) in children and young adults and Gilead’s axicabtagene ciloleucel (YescartaⓇ) was approved one month later, in October 2018, for the treatment of large B cell lymphoma.
The two approved CAR-T therapies both target CD19, an antigen found on the membrane of B cells. Also known as B lymphocytes, B cells are a type of white blood cell that secretes antibodies.
“CD19 is found on all B cells, not only cancerous B cells,” explains Barzel. “So when one uses CAR against CD19, one eliminates all B cells including the tumor. Fortunately, one can live without B cells for a while and there are ways to reduce the risk of infection in the meantime. In the long run, after the cancer is gone, the B cells regenerate. That is why CD19 is an easy target. It is also found in so many cells in our blood, that the activation of the injected T cells is very potent. It’s both very potent and relatively safe.”
Challenges in T cell engineering
To date, engineered T cells have only been approved for the treatment of liquid tumors. The main reason is the choice of antigen. While CD19 is easily targeted, most solid tumor antigens are hard to target.
“It is very difficult to find an antigen that is located on the solid tumor and only on the solid tumor. Engineered T cells might attack healthy cells that express the same antigen,” says Barzel. “In addition, these antigens are found in the microenvironment of the tumor, which is often subjected to immune suppression. In order to engage with the antigen, the T cells have to move into the tumor where they are counteracted by many different mechanisms the cancer can throw at them.”
Today, T cells may be engineered with additional moieties that can oppose this suppression, or alternatively, patients may receive a combination of therapies, in which T cells are combined with antibodies or small drugs that target the suppression by the tumor microenvironment.
Allogeneic T cell engineering and its pitfalls
“Yet another major challenge in the development of T cell therapies is scalability,” Barzel explains. “Treatments approved so far involve autologous engineering. The T cells are taken from the patient, engineered and expanded in the lab, and reinjected into those same patients. This takes a lot of time and money and requires special facilities that are not found in every hospital.”
Furthermore, due to the cancer and to previous treatments, the patient may already have a very depleted immune system. This means that it can be hard to find sufficient autologous T cells to serve as the basis of the engineering technique. To solve these problems, researchers are working on allogeneic T cell engineering, where the T cells of a donor are engineered, banked, preserved and injected into a recipient patient when needed.
Although allogeneic T cell engineering is more scalable and cheaper than autologous engineering, there is a risk of Graft-versus-host disease. In Graft-versus-host disease, the T cells of the donor attack the recipient. To avoid this from occurring, researchers have developed additional engineering techniques aimed at preventing the expression of the endogenous receptor, the receptor that causes Graft-vs-host.
Rejection is another problem that researchers are currently working on. “T cells of the donor may be recognized by the recipient as foreign and therefore might have a very short half-life in the recipient body because they will be eliminated by the endogenous immune system,” Barzel explains. “Several researchers are trying to prevent this by stopping the expression of the major histocompatibility complex (MHC) – the genes that code for cell surface proteins – on the donor T cells so the recipient T cells will not attack the donor T cells.”
However, with the MHC gone, the recipients natural killer (NK) cells can recognize and attack the donor T cells as well. “It’s a double-edged sword,” Barzel points out. “Researchers are currently looking for ways around the problem, for example, by toning down the NK response against donor T cells.”
In vivo T cell engineering, the future of T cell therapy?
Barzel does not believe that the future of T cell therapy lies in autologous or allogeneic T cell engineering. “I believe the answer will be in vivo viral vector injection. This would mean that T cells are engineered inside the body of the patient. There would be no risk of Graft-versus-host disease or rejection and no scalability issues because these are the recipients own T cells. This is a cutting-edge approach, it has many challenges of its own, but this is where I see the future of T cell therapy.”
Barzel and his team are working on several different solutions on how to perform in vivo T cell engineering. For example, they are looking at different injection locations that contain many T cells, such as the thymus and the spleen. They are also studying different viral vectors, like adeno-associated viral (AAV) vectors that have been proven to be safe and efficacious in vivo.
“We are using AAV vectors because retroviral vectors and lentiviral vectors, which are more commonly used in the context of immunotherapy, have some safety and half-life issues in vivo,” says Barzel. “But AAV is not naturally prone to integration. So if one wants stable expression in dividing T cells, one has to devise different ways of how the receptor gene – the CAR gene or TCR gene – is to be integrated from the non-integrating AAV vector into the genome of the T cell. We are working on several such methods, some of these involve nucleases, such as CRISPR.”
Discussing immunotherapies at the International Conference on Lymphocyte Engineering
Barzel and other experts on T cells and T cell engineering worldwide will be speaking at the International Conference on Lymphocyte Engineering (ICLE) 2019 in London in September, alongside representatives from a number of institutions and leading companies.
Immunologist and oncologist Carl June will be one of the high-profile keynote speakers at this year’s ICLE. He is currently the Richard W. Vague Professor in Immunotherapy and Director of the Center for Cellular Immunotherapies at Perelman School of Medicine and Director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania, USA.
The other two keynote speakers are immunologist and physician Nicholas Restifo, Director of the Center for Cancer Research and Head of the Center of Excellence in Immunology at the National Cancer Institute and the National Institutes of Health in Bethesda, Maryland, USA; and CAR-T therapy expert Stanley Riddell, Director of the Immunotherapy Integrated Research Center at the Fred Hutchinson Cancer Research Center and Professor of the Department of Medicine at the University of Washington, USA.
In his talk, Barzel will focus on his research and his thoughts on the future of T cell engineering. “One focus of my presentation will be in vivo engineering; how it is that we inject, what vectors we use, what we code in them,” Barzel explains. “The other focus will be how other types of lymphocytes can also be engineered, which can be helpful for immunotherapies for cancer but also for infectious diseases. More specifically, my lab now also engineers B cells, the other arm of the humoral immune response. And I believe that B cells expressing antibodies can play a major part in the future of immunotherapy.”
Be a part of the promising future of T cell engineering and join the world’s renowned health innovators in immuno-gene therapy for the 2nd International Conference on Lymphocyte Engineering from 13-15 September in London, UK! Sign up today!
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Author: Larissa Warneck, Science Journalist at Labiotech.eu