Our own immune T-cells can be one of the best defense lines against cancer. Walloon biopharmaceutical company Celyad is using an innovative approach to harness a patient's own immune system to direct it specifically against a disease.
Chimeric Antigen Receptor (CAR) T-cell therapy is based on NKG2D, an activating receptor found on the surface of Natural Killer Cells (NK cells). Ligands that bind to the NKG2D receptor activate NK cells that lyse the susceptible ligand-expressing cancer cells and are naturally produced by many cancer cells. However, some tumour cells manage to evade the NKG2D response. This body's natural NKG2D defense mechanism can be engineered to specifically recognize cancer antigens, so no cancer cells are able to evade this immunological response.
Training the immune system to kill cancer
In CAR T-cell therapy, a patient’s T-cells are collected and engineered to express an “improved” version of NKG2D receptor on their cell surface. The engineered CAR T-cells are then infused back into the patient’s body where, with guidance from the chimeric receptor, they recognize and kill cancer cells that are expressing a tumor antigen (e.g. CD19) on their surface. The newest CARs have two co-stimulatory domains to increase their potency. When the engineered CAR T-cells engage the target antigen, it triggers further multiplication of the cells in the body, and activation of a cytotoxic response. Additionally, the CAR T-cells have an auto-regulatory capability, as they are only able to multiply in the presence of the target antigen.
Not only for blood cancers
A phase 1 clinical trial of NKG2D CAR T-cell therapy for the treatment of leukemia or myeloma has been initiated. After the 30-day follow-up of the first patient infused with engineered CAR T-cells, no short-term adverse events were observed, and so based on this safety data, two additional patients will be enrolled. The data read-out from this clinical trial is expected by the middle of 2016. In addition to the blood cancers targeted in the clinical trials, NKG2D CAR T-Cell therapy could be also used for treatment of solid tumors. “As NKG2D ligands are expressed by numerous tumor cells: ovarian, prostate, bladder, breast, lung, liver, leukemia and others, NKG2D CAR T-Cell therapy can therefore not only fight blood cancers but also solid tumors,” comments Christian Homsy, Celyad’s CEO. “As soon as the safety and efficacy of NKG2D CAR T-cell treatment is demonstrated in our on-going clinical trial, we intend to further investigate additional therapeutic indications, for both liquid and solid tumors. Due to the versatility of the NKG2D ligand expression pattern, expansion beyond cancer to chronic infectious diseases may also be planned.”
Using cells from “non-self” donors to reach more patients
CAR T-cells can either have an autologous or an allogeneic origin. Autologous CAR T-cells are engineered from the patient's T-cells, and so they match the patient's immune system. This prevents destruction of the T-cells from the host immune system and prevents autoimmune reactions, where host tissue is attacked in a non-specific manner. Allogeneic cells, on the other hand, are from a "non-self" donor. These cells must be specifically modified to match the patient's immune system. The injection of allogeneic T-cells into a patient normally leads to a severe rejection response, mostly due to the T cell receptors (TCR) on their surface. The reaction between TCRs and antigens, which are bound to the autologous major histocompatibility complex, will determine the donor’s compatibility for the T-cell transplantation. To overcome this issue and avoid rejection of the transplanted cells, Celyad modifies allogeneic T-cells from healthy donors to express, in addition to CAR, TCR Inhibitory Molecules (TIMs). “The pre-clinical data supporting this technology is exceptionally strong. We plan to be in a position to start human trials for allogeneic therapies with CAR NKG2D in 2016” explains Christian Homsy. The advantage of an allogeneic platform is that it would allow production “off-the-shelf” CAR T-cell products to treat thousands of cancer patients.
More effective than traditional therapies
Based on pre-clinical data, CAR T-cell therapy seems to be significantly more effective than current treatment options for hematological cancers. This development could bring hope to patients, for which no treatment is currently available. Furthermore, there is hope that this technology will be applicable to many other blood cancers and solid tumors, as the target of the CAR T-cells can be manipulated to target the tumor of interest.
From heart to CAR T
Celyad was founded by Christian Homsy in 2007 as Cardio3 BioSciences. The company was established based on research collaboration with the Mayo Clinic (MN, USA). Its clinical programs initially targeted only cardiovascular diseases but early in 2015, with the acquisition of OnCyte, a division of Celdara Medical, the Company moved into one of the most promising fields of cancer treatment today: CAR T-cell therapy. To better reflect the broadening the spectrum of the offered cell based therapies and expansion into the field of oncology; Cardio3 BioSciences changed its name to Celyad.