Our immune system keeps track of all the molecules commonly found in our body. Any unusual or new molecule that the immune system can't identify initiates a warning, letting our immunity to attack it.
In the case of cancer cells, usually, a single cell goes through random changes called mutations which cause this cell to proliferate uncontrollably. These mutations also let new forms of molecules to appear on the surface of the cancer cells.
CAR T-cell therapy is a promising method to modify a type of white blood cell named T cells to spot the molecules on the surface of cancer cells and attack them. This is done by transforming them in the lab so they can find and destroy cancer cells very specifically and efficiently. The T-cells used in CAR T-cell therapies get changed in the lab to identify specific cancer cells by linking a man-designed receptor named chimeric antigen receptor or CAR.
Cell Therapy in Transplantation
Solid-organ transplantations such as liver and lung are the treatment of choice for patients with end-stage organ dysfunction.
Over the last decade, vascularized composite allotransplantation (VCA), the transplantation of face and limbs from a deceased donor, has become a good alternative for the reconstruction of devastating injuries of these specialized tissues. VCA represents a unique new treatment option for severe soft tissue defects following burn injury to achieve both psychosocial and functional rehabilitation.
Although we have observed many advancements in short-term outcomes of transplantation, the longterm outcome is not that favorable as the results of multiple morbidities and mortalities related to the toxicity of immunosuppressive drugs. As such, the focus of the researcher and clinicians is focused on developing innovative strategies to achieve immune tolerance, a state whereby the immune system of the recipient can be trained to allow the allograft, preventing the necessity of life-long immunosuppressive regimen. Indeed, there are rare reports of spontaneous tolerance, whereby the recipient patients are off the immunosuppressive drugs, and preserving proper allograft for both liver and kidney transplantations. Nevertheless, this is a very uncommon happening and happens very late after transplantation.
On the other hand, the majority of patients continued on life-long immunosuppression to prevent allograft rejection. As such, significant research has focused on immune regulation in the context of organ transplantation with cell therapy and mixed chimerism known as methods holding significant promise in these efforts.
Our group has established expertise in tolerance induction through the development of a highly promising mixed chimerism protocol for VCA transplants. Mixed chimerism is the use of a donor hematopoietic stem cell transplant (HSCT) along with a VCA to induce a hybrid immune system in the recipient that recognizes the donor VCA as “self” and therefore does not reject it. The difficulty in achieving durable mixed chimerism and graft acceptance is the presence of high levels of specific T cells that are known to hinder tolerance induction in sensitized recipients. Our strategy for achieving stable mixed chimerism is to utilize advanced engineering techniques to generate T cell therapeutics to specifically suppress the recipients' immune cells that are reactive against the donor bone marrow and tissue cells and spare the rest of their immunity and therefore cause no immunosuppression.
Musculoskeletal extremity injuries, including traumatic amputations, are frequently seen in our pediatric burn and trauma population. These patients often struggle with severe functional and psychosocial challenges and decreased quality and quantity of life. The addition of immunomodulatory strategies such as our approach for VCA would allow more widespread use of these procedures among the patients.
The potential applications of this approach go far beyond VCA and could be applicable for immunosuppressant-free solid organ transplantation.
Interestingly, we have shown that this approach is effective in helping to induce tolerance in autoimmune conditions like Type 1 Diabetes and Alopecia as well.