- It is a new type of immunotherapy for treatment of various cancers.
- It involves training of the immune system to fight cancer thus has minimal side effects.
- It is already approved for some resistant and aggressive kind of blood cancers.
- Hundreds of trials are underway for cancers of various organs like lungs, ovaries, gut, and initial results are promising.
- It is one of the most prospective anticancer therapies that may help in just any type of cancer.
For several decades surgical removal of the tumor followed by the destruction of remaining cancer cells with the help of radiation therapy and chemotherapy has been the mainstay of cancer treatment. Chemotherapeutic drugs are quite toxic and only partially selective. Thus they kill not only cancer cells, but also healthy cells of the body resulting in a wide range of side effects. Immunotherapy is the highly specific approach, it is a strategy of training the body’s immune system to attack cancer cell exclusively, and thus it is highly efficient and yet minimally toxic to the body.
You can be a victim of cancer, or a survivor of cancer. It’s a mindset.
What is Car-T therapy?
Our immune system has various cells that help us to fight infections, multiple diseases. Immune cells would attack anything that does not normally belong to the body. However, recognizing cancer cells is more complicated as they have outgrown from the healthy body cells, these are mutated cell that divide and spread uncontrollably. Since our immune system does not consider them as outsiders or risk for health, it does not attack or kill them.
Researchers are using various techniques to train the immune cells to identify the cancer cells and start attacking them. Immune therapy is the process of stimulating intrinsic immune system to act against the cancer cells. For the purpose researchers are using various techniques like developing vaccines, using monoclonal antibodies, non-specific immune stimulation, use of T-cells in the therapy. 1
In creating anti-cancer vaccines researchers extract the cancer cells and unmask them so that immune system can recognize them, then these unmasked cells are injected into the person living with cancer. 2 While monoclonal antibodies are biological compounds that can identify cancer cells and flag them so that the immune cells like T-cells can neutralize them. 3
T-cells are white blood cells that originate in bone marrow but mature in the thymus (that is why called T-cells). They play various roles in immunity, they may directly neutralize numerous infections (cytotoxic T-cells) or foreign substances, or they can release materials called cytokines thus asking help from another type of cells in neutralizing the enemies. It is the T-cells that tell the B-cells to release antibodies against infections or cancers; they are also responsible for instructing macrophages to eat up cancer cells or infections. 4
Car-T/ CAR T-cell therapy is about teaching the T-cells of immune system to identify and kill cancer cells. 5
How does it work?
Creation of vaccines to treat infective disease in the 18th century could be regarded as the beginning of current immunotherapeutics. The effectiveness of vaccines proved that immune system could be trained or efficiently retrained to fight ailments. However, use of immunotherapy had to wait for other technical advances, and it became a reality only in the 1980s. 6
For the development of CAR T-cell therapy, first, the venous blood is extracted from the patient who is living with cancer. Next step in treatment is extraction or isolation of T-cells from the patient’s blood. Once the almost pure cells are available, they are genetically modified with the help of gene engineering so that they could identify and bind to the cancer cells. It is achieved by inserting the unique receptor gene into the T-cells. This specific receptor is named chimeric antigen receptor (CAR). So the end product of the process is CAR T-cells. 7
Once the CAR T-cells have been created, they are multiplied in the laboratory conditions, so that there is enough quantity to fight cancer. Finally, these CAR T-cells are injected back to the patient. These reinjected, modified, retrained cells can identify the cancer cells in the body, and thus they can initiate the cascade of the immune response, which results in the neutralization of the cancer cells.
Such therapy has the benefit of extreme selectivity. It means that modified T-cells only kills the cancer cells. Thus the treatment is safe for healthy cells.
How much time does it take to cure cancers when treated with Car-T?
How long it takes to treat cancer would depend on the location of cancer, type of cancer, and stage of cancer. Usually, the response to the various blood cancers is faster and better when compared to solid tumors of other organs. 8 Theoretically such kind of therapy must work within hours of injection of CAR T-cells, and maximum immune response must be initiated within few days.
However, in practical things are entirely different, as cancer cells have their ways of masking. Thus in many cases, CAR T-cell therapy may take longer to work, or there may be need to take other complementary drugs to increase the efficiency of the treatment.
What are the possible side effects of CAR-T cell therapy?
CAR-T cell therapy has certain associated risks. In some individuals, CAR T-cells may fail to identify the cancer cells. Instead CAR T-cells may start attacking the healthy cells, simply said, CAR T-cells may get confused between cancer cells and healthy cells due to similarities between them, that may result in autoimmune disease.
Even when the therapy is effective, destruction of cancer cells may release toxins that may cause fever, hypotension and other reactions. 9
Studies in Animals and observations till date
Animal studies of CAR T-cells started in the 1990s, and many of them demonstrated good results in the treatment of various blood cancers. Later animal studies focused on the treatment of solid tumors of the liver, colon, brain, and other organs. Since the results of the animal trials were encouraging, human studies were initiated. 10
Studies in Humans and observations till date
Human trials of CAR T-cells started in the early 1990s, but it really gained momentum from the year 2000 onwards, and till date, hundreds of trials have been done in humans for various cancers and with varied results. CAR T-cells creating technology is improving day by day, at present these trials for CAR T-cells are divided into four generations.
Trials of generation one and two CAR T-cells were mostly for lymphomas and other hematological malignancies, while third and four generation CAR T-cells are also being tested for solid tumors like ovary tumor, brain tumor, or breast cancer. At present, the results can be described as mixed, though they are improving with each generation of CAR T-cells. 11
Presently, more than 200 clinical trials deploying CAR T-cells are underway in the US, Europe, Australia, China, and some other Asian nations. 12 Some of the trials have shown excellent results in different blood cancers with remissions rates as high as 90%. 13 Latest clinical trials are increasingly focusing on the solid tumors of ovaries, breasts, gastrointestinal tracts, lungs, various malignancies of the brain, to name the few. Though the success in solid tumors is limited, however, things are improving fast.
One of the challenges in trials with solid tumors of various organs is the difficulty in the delivery of CAR T-cells. In case of blood cells systemic delivery is an excellent choice, but this mode of delivery is far less efficient for the cancers of various internal organs. Thus for example CAR T-cells may not reach the brain tumor if injected intravenously. Therefore researchers are trying to find out the more efficient ways of delivery, and one of the strategies is regional deliver, that is infusing the CAR T-cells in the organs infested by the cancer. 14
Is there a possibility to participate in the trials? If yes, what is the process?
If one is suffering from some cancer that cannot be treated with presently available therapies it makes sense to become part of the ongoing research. Although there is a high risk of toxicity and complications, but there are also chances of getting cured. At present more than 300 different sites are recruiting cancer patients for CAR T-cells trials. One can search for more information on website clinicaltrials.gov or find information here. 15
When will Car-T therapy be available for public?
It will still take few years before the use of CAR T-cells become widespread for various ailments in the US or other countries. Before being approved any new treatment, modality has to go through three stages of clinical trials. The first phase is about testing safety in a small group of humans, the second phase is about testing effectiveness in much larger numbers, and the third phase is for testing both the effectiveness and safety in a much large number of patients, usually third phase trial is carried out in hundreds of people. Each phase takes from several months to years. Considering that hundreds of trials are ongoing for various cancers, it is quite probable that some of them will make to the market in coming five years.
At present CAR T-cell therapies are approved only for two conditions in the US, first is the acute lymphoblastic leukemia of young adults and children, and second is B-cell lymphoma. 16
CAR T-cell therapy is still in its early days. However, it is one of the fastest evolving anticancer therapeutic approaches and perhaps the most promising too. It has come a long way from its early days in the 1990s. Today researchers have the much more profound knowledge, and they are equipped with far better technology, something that is visible from the entry of CAR T-cells into the fourth generation. Initial results of hundreds of trials are already coming, and they are highly encouraging. It seems that CAR T-cell therapy may soon become one of the primary therapeutic options for the treatment of various blood cancers. Despite the setbacks in trials of solid tumors of various internal organs, things are improving fast, and we may probably see some approvals in the coming years.
Coulson A, Levy A, Gossell-Williams M. Monoclonal Antibodies in Cancer Therapy: Mechanisms, Successes and Limitations. West Indian Med J. 2014;63(6):650-654. doi:10.7727/wimj.2013.241↩
Decker WK, da Silva RF, Sanabria MH, et al. Cancer Immunotherapy: Historical Perspective of a Clinical Revolution and Emerging Preclinical Animal Models. Front Immunol. 2017;8. doi:10.3389/fimmu.2017.00829↩
Kershaw MH, Teng MWL, Smyth MJ, Darcy PK. Supernatural T cells: genetic modification of T cells for cancer therapy. Nat Rev Immunol. 2005;5(12):928-940. doi:10.1038/nri1729↩
Grigor EJM, Fergusson DA, Haggar F, et al. Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in patients with haematological and solid malignancies: protocol for a systematic review and meta-analysis. BMJ Open. 2017;7(12):e019321. doi:10.1136/bmjopen-2017-019321↩
Smith AJ, Oertle J, Warren D, Prato D. Chimeric antigen receptor (CAR) T cell therapy for malignant cancers: Summary and perspective. J Cell Immunother. 2016;2(2):59-68. doi:10.1016/j.jocit.2016.08.001↩
Wu Y, Xu R, Jia K, Shi H. The efficacy of chimeric antigen receptor (CAR) immunotherapy in animal models for solid tumors: A systematic review and meta-analysis. PLOS ONE. 2017;12(11):e0187902. doi:10.1371/journal.pone.0187902↩
Curran KJ, Pegram HJ, Brentjens RJ. Chimeric Antigen Receptors for T cell Immunotherapy: Current Understanding and Future Direction. J Gene Med. 2012;14(6):405-415. doi:10.1002/jgm.2604↩
Hartmann J, Schüßler‐Lenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med. July 2017:e201607485. doi:10.15252/emmm.201607485↩
Xia A-L, Wang X-C, Lu Y-J, Lu X-J, Sun B. Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: challenges and opportunities. Oncotarget. 2017;8(52):90521-90531. doi:10.18632/oncotarget.19361↩
Sridhar P, Petrocca F. Regional Delivery of Chimeric Antigen Receptor (CAR) T-Cells for Cancer Therapy. Cancers. 2017;9(7). doi:10.3390/cancers9070092↩