CAR T Cell Therapy: Promising Cancer Immunotherapy

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CAR T-cell therapy, also known as chimeric antigen receptor T-cell therapy, is a type of immunotherapy that uses modified T cells, a type of white blood cell, to treat some cancers. The T cells are collected from the patient's blood and modified to express a chimeric antigen receptor (CAR) designed to recognize a specific protein on the cancer cells. The CAR directs the T cells to destroy the cancer cells. Once infused back into the patient, the CAR T cells multiply and stay engaged against the cancer cells for a sustained period of time. This form of treatment is considered personalized medicine as it uses the patient's own immune system cells to fight their cancer.

How does it Work?

The process begins by collecting T cells from the patient through a process called leukapheresis. These T cells are then taken to the lab and genetically engineered using a viral or non-viral vector to produce chimeric antigen receptors (CARs) on their surface. A CAR consists of an extracellular domain made up of an antibody-derived protein that recognizes a specific target on tumor cells, a transmembrane domain, and an intracellular domain that contains signaling proteins from the T cell receptor complex. This intracellular domain is important because it activates the T cell after it recognizes the target antigen.

Coherent Market Insights talks more about it in CAR T-cell therapy Market.

Once the CAR T cells are engineered, they are grown and expanded in number in the lab. These genetically modified CAR T cells are then infused back into the patient through intravenous administration. The CAR directs the T cells to only recognize and destroy cancer cells that express the specific target antigen. This provides the ability for precise targeting of tumor cells while sparing normal tissues. Once reinfused, the CAR T cells accumulate in the blood and infiltrate the tumor microenvironment where they multiply in huge numbers and battle the cancer cells through direct killing and secretion of inflammatory cytokines.

Applications & Targets of CAR T Cell Therapy

While CAR T cell therapy is still considered experimental, it has gained significant success in treating hematological cancers such as leukemia and lymphoma. Some of the notable applications and targets include:

- Acute Lymphoblastic Leukemia (ALL): CD19 is a protein highly expressed in ALL. Anti-CD19 CAR T cells have produced high remission rates in relapsed/refractory ALL patients in clinical trials. Tisagenlecleucel (Kymriah) became the first FDA approved CAR T therapy in 2017 for refractory ALL in children and young adults.

- Large B Cell Lymphoma: Likewise CD19 CAR T cells have shown huge promise in treating aggressive forms of non-Hodgkin's lymphoma like Diffuse Large B-Cell Lymphoma in pivotal trials. Yescarta became the first CAR T therapy approved for treating relapsed/refractory large B cell lymphoma in adults in 2017.

- Chronic Lymphocytic Leukemia (CLL): Other B cell antigens like CD20 and CD23 are being targeted for CLL. Early trials indicate safety and effectiveness against this common leukemia of elderly patients.

- Multiple Myeloma: SLAMF7 is highly expressed in plasma cells and multiple myeloma. Anti-SLAMF7 CAR T therapies are in development to target this often fatal blood cancer.

- Solid Tumors: Advanced research efforts are exploring CAR T therapy for solid tumors by targeting antigens like HER2, EGFR, mesothelin, CEA etc. Challenges include immunosuppressive tumor microenvironment and antigen heterogeneity.

CAR T Cell Therapy Mechanisms & Side Effects

The actual mechanism of action involves CAR T cells traveling through the bloodstream and getting activated upon recognition of the target antigen on cancer cells. They proliferate massively at the tumor site and directly kill cancer cells through cytotoxic granules like perforin and granzymes. They also induce apoptosis through Fas/Fas ligand interaction. Additionally, CAR T cells secrete inflammatory cytokines like IFN-γ and TNF-α which activate other immune cells to join the anti-tumor response.

However, this robust activation and proliferation of CAR T cells can sometimes lead to life-threatening side effects in a minority of patients called cytokine release syndrome (CRS). CRS occurs due to a "cytokine storm" and can cause high fever, low blood pressure, difficulty breathing etc. Other potential toxicities include neurotoxicity manifested as confusion, dizziness or delirium, B-cell aplasia, and on-target/off-tumor toxicity if the target antigen is also expressed on normal tissues. Most adverse effects are acute and manageable with supportive care and cytokine-blockade such as with tocilizumab.

Optimizing CAR T Cell Therapy

Scientists are continuously working on strategies to optimize CAR T cell effectiveness and safety. Areas of research include improving T cell fitness and persistence through tumor microenvironment modifying agents or costimulatory domains in CAR design. Gene editing technologies like CRISPR-Cas9 are enabling insertion of multiple CAR genes, suicide genes for safety, or elimination of inhibitory pathways. Combination with checkpoint inhibitors or other immunotherapies holds promise. Universal "Plug and Play" platforms are allowing rapid generation of novel CAR T cell products against new targets. Adoptive cell therapies have immense potential to cure formerly incurable cancers and research is still unveiling new applications on the horizon.

Regulatory Landscape and Market Outlook

The positive clinical data from CAR T cell therapy trials has prompted regulatory approvals from the United States FDA and European Medicines Agency in recent years. Yescarta and Kymriah gained regular approval for treating relapsed/refractory lymphoma and ALL respectively. As commercial products they have generated billions in revenues. More approvals are expected based on ongoing late phase trials evaluating additional CAR T therapies and cancer types.

With over 20,000 new clinical trials registered globally each year, CAR T cell therapy research continues at a breakneck pace across both hematological and solid tumors. The leading regions actively researching CAR T are North America, Europe, China, and parts of Asia Pacific. Though the technology is still maturing, the global CAR T cell therapy market is projected to grow substantially in the coming decade backed by more approvals and strategic partnerships between biotech companies and major pharma players (see Coherent Market Insights for more details). Widespread adoption in community centers versus select academic institutions will determine real-world clinical benefit and market access over time. Overall, CAR T cells represent one of the most promising areas of cancer immunotherapy today.