CAR-T Cell Therapy-The Near Miracle Cure for Cancer
On the development of technology that could decrease the side effects leading to a more targeted approach in cancer treatment, Chimeric antigen receptor (CAR)-T cell (CAR-T) immunotherapy is ready to steer the wheels in a whole new direction. However, there is debate that whether it is a miracle therapy to cure cancer? Lets read about it in this featured review and make our opinion..
Before knowing about any breakthrough researches and innovations related to CAR-T cell therapy, lets strengthen our basics about CAR-T first.
T-cells are the lymphocytes which evoke cell mediated immune response in the body. These cells mature in the thymus from thymocytes, hence called T-cells. These cells directly attack the invaders and hunts them down without involvement of any antibodies. They have the innate capacity to recognize any foreign invaders or any infected cells present in the body and can destroy them without disturbing the other cells.
Now talking about the CAR, they are recombinant receptors for antigen which can perform the antigen binding as well as T cell activating function. These receptors are called chimeric as it is comprised of different parts from distinct sources.
Altogether they have been remodelled and directed as CAR-T cell therapy- a potent immunotherapeutic tool to fight cancer .
In this immunomodulatory technique body’s own immune cells are trained and developed into immunocompetent soldiers. The immune system of a cancer patient gets compromised gradually leading to attack of various opportunistic infections and diseases. Cancer cells attacks bone marrow, the primary sight for haematopoiesis which irregulates the new blood synthesis or lymphocytes production therefore creating obstacle in immune system regulation.
In the breakthrough of CAR-T cell immunotherapy, the genetic re-targeting of T-cells are done as follows:-
- Blood samples are taken from the patient and the healthy T-cells are extracted from it.
- These T-cells are genetically engineered in the laboratory to develop CAR on its surface.
- These revised ‘CAR-T cells’ are empowered to recognize the specific tumor cells antigen.
- These CAR-T cells are then grown and multiplied in a controlled conditions upto a definite amount and then reinjected into the patients body where these trained soldiers multiply in the bloodstream and destroy the tumor cells with the targeted antigen leading to remission of cancer.
When the blood sample is taken from the patient’s own body, it is called autologous CAR technology which can be costly but their is no chance of immune rejection in this case.
The other method is allogenic CAR technology growing CAR-T cells in donor blood samples. This technique is cheaper but with the chances of immune rejection.
Figure 1. How engineered T‐cell therapy works in practice. (Image courtesy: The Stiliyan Petrov Foundation (SPF) with reference to the Department of Haematology at the University College London, United Kingdom).
The CAR technique was pioneered by the Zelig Eshhar, chemist and immunologist at Weizmann Institute of Science, Israel. In 1990 CAR was developed by Eshhar with Steven Rosenberg to target human melanoma at the National Institute of Health.
CAR-T cell therapy has definitely promised to reduce the side effects caused by the other existing forms of cancer treatment. Their target specific action can prevent the healthy cells of the body from getting damaged but on the other hand itself impose a chance of different side effects- cytokine-release syndrome, tumor-lysis syndrome, B-cell aplasia and liver toxicity.
However, CAR-T cell trial studies have shown promising results in patients with relapsed/refractory acute lymphoblastic leukemia, non-Hodgkin lymphoma and in advanced and high risk chronic lymphocytic leukemia.
Depending upon the number of additional intercellular signalling domain these CAR-T cells can be of different types like: First generation CAR-T cells having no additional signalling domain; Second generation CAR-T cells having one additional signalling domain and third generation CAR-T cells having two additional signalling domains.
Along with prior conditioning chemotherapy this CAR-T cell technique is used because these conventional methods (radiation and chemotherapy) helps in eliminating endogenous cells that compete with modified CAR-T cells for cytokines. Hence, they aid in CAR-T therapy.
CD19, CD20, CD22, ROR1 etc. are the most common tumour antigens that are generally present in both malignant and non-malignant tumours. Currently this technique is used mainly for B-cell related blood cancer by targeting CD19 tumour antigen.
Companies and CAR-T Cell Therapy
The CAR-T technology is still in its infancy but a rush of enthusiasm has been seen in the companies for the technology and bucked up by some previous positive results, various pharmaceutical and biotechnology companies are investing in this technology.
In 2011, clinical results including complete remission from terminal cancer patients was first achieved by Novartis. Lately, Novartis lead CAR-T cell therapy candidate CTL019 showed positive results of 47% of overall response rate (ORR) in 3 months in diffuse large B-cell Lymphoma and 73 % in follicular lymphoma in its Phase IIa clinical study.
Presently, Juno therapeutics six CD-19 (lead product candidate) targeting CAR-T cell therapy for various medical condition like relapsed or refractory chronic lymphocytic leukemia, non-Hodgkin’s lymphoma and its subtypes or acute lymphoblastic leukemia are under clinical trials. Also, they are working on second generation CAR-technology or the “armored CAR technology” in which CAR cells are tagged with some signalling protein IL-12 that stimulates T-cell activation while inhibiting the surrounding tumour microenvironment. The one amongst the pioneers of CAR-T cell therapies has also collaborated with Celgene and Editas Medicine to accelerate the development and commercialization of CAR-T and TCR cell therapies.
Bellicum pharmaceutical, Texas has been working on a modified and controllable version of CAR called GoCAR-T technology which is projected as a more controlled version of CAR-T therapy. Go CAR-T cells are fully activated only in the presence of both the cancer cells and rimiducid. Therefore their degree of activation in the body can be controlled by the amount of administration of rimiducid.
Recently, Roche and Kite Pharma signed a combo deal for Kite’s CAR-technology based lead candidate KTE-C19 for aggressive non-Hodgkin’s lymphoma targeting CD19 antigens expressed in B-cell lymphomas and Roche’s Atezolizumab mAb designed to target PD-L1 expressed over tumour cells. Their strategic alliance looked forward for some encouraging combined results of the two different candidates.
Similarly Kite also entered into a huge collaboration with Amgen and licence agreement to develop and commercialice the Kite’s CAR T cell therapy platform together globally.
Cellectis “ off-the-shelf” allogeneic modified product UCART19 (Universal Chimeric Antigene Receptor T cells ) was successful in treating an 11 months old baby girl with leukemia clearing her symptoms miraculously in two months. Cellectis was in partnership with Pfizer in making off-the-shelf CAR-T cells that can be used immediately or the allogeneic method in which a single healthy donor would be enough to supply multiple number of patients and it will be cheaper than autologous method. Recently, Cellectis has granted rights to Servier (a French pharmaceutical company) for commercializing its cancer immunotherapy UCART019.
Recently, Baxalta and Precision BioSciences are planning to develop an allogenic CAR-T therapies for targeting up to six unique targets. It is expected that their first program will enter to clinical trials at the end of 2017 in which, Precision BioSciences will be responsible for early stage trials up to Phase II and rest of the late stage trials will be conducted by Baxalta.
Ziopharm Oncology is also exploring the possibilities of CAR-T cell therapy in hematologic malignancies to wide range of target including solid tumors.
In addition to monotherapies researchers are planning to combine CAR-technology along with other technologies like checkpoint inhibitors, programmed death (PD-1) and anti-CTLA4 (anti-cytotoxic T-lymphocyte antigen 4).
Ultimately, I am at the conclusion that while CAR-T cell therapy hold tremendous potential for cancer cure, yet it has long way to go and will depend on the results of the ongoing clinical trials. But with success which it has already achieved, it can be said that it is a near miracle therapy which is progressing very fast towards becoming the miracle to cure cancer.
Featured image credit: Healthcare Industry and Vaccine Research. Conceptual Illustration. © georgepontinojr (Stock Photo ID: 66229444)