There is currently a lot of excitement surrounding CAR-T therapy which is one form of Adoptive Cell Therapy (ACT). It has the potential to be the ultimate personalized therapy: T cells can be genetically engineered to have specificity to virtually any antigen. As a result, a patient’s own T cells can target and destroy cancerous cells with a high degree of specificity.
ADOPTIVE CELL THERAPY
The basic principle is to rapidly generate T-cells targeted to a specific tumour-antigen.
We have known about the unique theoretical benefits of T cell therapy for decades:
We now realise that allogenic hematopoietic stem cell transplantation used for leukemia was an early example of adoptive T cell therapy. The donor cells mediate a graft-versus-tumour effect against allogenic antigens present on leukemic cells. However, the response is non-specific and there would also be graft-on-host effect too. Now we can achieve greater specificity with adoptive cell therapy by isolating lymphocytes from a patient’s blood and expanding them outside the body before reinfusing into the patient.
We have known about the unique theoretical benefits of T cell therapy for decades:
- T cell responses are specific to an antigen and can therefore potentially differentiate between self and tumour cells.
- T cell responses are robust: following activation there can be 1000-fold clonal expansion of T cells.
- They could treat distant metastases as T-cells circulate systemically.
- T cell responses have memory and treatment effect could be maintained.
We now realise that allogenic hematopoietic stem cell transplantation used for leukemia was an early example of adoptive T cell therapy. The donor cells mediate a graft-versus-tumour effect against allogenic antigens present on leukemic cells. However, the response is non-specific and there would also be graft-on-host effect too. Now we can achieve greater specificity with adoptive cell therapy by isolating lymphocytes from a patient’s blood and expanding them outside the body before reinfusing into the patient.
HOW CAR-T cells are made
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A quick and simple overview of the theory
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Progress so far
Before CAR-T therapy, T cells were engineered to express T cells receptors (TCR) to be specific to antigens present on MHC molecules on cancer cells. The excitement of chimeric antigen receptors (CARs) is that they are MHC independent. CARs involve an immunoglobulin variable domain being fused to a T cell receptor constant domain. This allows T cells to target any cell target antigen not just those on MHC class molecules drastically increasing the potential targets.
Overtime, research has allowed engineered to T cells to produce more T cells when infused into the patient (so called expansion) and survive longer in the circulation (termed persistence). As a result, CAR-T therapy has been described as a ‘living drug’.
CAR-T cells production time has reduced from several weeks to less than 1 week currently.
They have been licensed by the FDA for relapsed or refractory diffuse large-B cell lymphoma and acute lymphoblastic leukemia in which CAR-T cells target CD19. In one of the earliest pivotal trials of CD19-targeted cells a complete response was seen in 27 of 30 patients with refractory ALL. However, through a phenomenon of ‘antigen loss’, one third of these patients will have ALL that reoccurs which no longer expressed CD19. Research is ongoing in to combination CAR-T treatment targeting multiple antigens in an effort to stop the emergence of resistant cancer cells.
Overtime, research has allowed engineered to T cells to produce more T cells when infused into the patient (so called expansion) and survive longer in the circulation (termed persistence). As a result, CAR-T therapy has been described as a ‘living drug’.
CAR-T cells production time has reduced from several weeks to less than 1 week currently.
They have been licensed by the FDA for relapsed or refractory diffuse large-B cell lymphoma and acute lymphoblastic leukemia in which CAR-T cells target CD19. In one of the earliest pivotal trials of CD19-targeted cells a complete response was seen in 27 of 30 patients with refractory ALL. However, through a phenomenon of ‘antigen loss’, one third of these patients will have ALL that reoccurs which no longer expressed CD19. Research is ongoing in to combination CAR-T treatment targeting multiple antigens in an effort to stop the emergence of resistant cancer cells.
Limitations
Side effects include cytokine release syndrome, neurological toxicity and on-target/off-tumour recognition (when a T cell identifies the correct antigen but on normal tissue). Cytokine release syndrome is a result of ‘on-target’ effect of CAR-T therapy and shows the T cells are active. It can lead to dangerous pyrexia and hypotension but can be normally be managed supportively with steroids but can include blocking cytokines directly, such as tocilizumab that blocks IL-6 directly.
CAR-T therapy is much more challenging in solid tumours due in part in failures to identify a unique antigen to target but also the complex interaction of the tumour microenvironment with the immune system.
CAR-T therapy proves a proof-of-concept of adoptive cell therapy, and immunotherapy more generally, with its dramatic results in some otherwise terminal hematological malignancies. As pharmaceutical investment increases the pace of improvements has surprised most commentators. However, the cost (currently in the US of $475,000 (£340,000) per patient) and availability remain major barriers to routine use of these therapies currently.
CAR-T therapy is much more challenging in solid tumours due in part in failures to identify a unique antigen to target but also the complex interaction of the tumour microenvironment with the immune system.
CAR-T therapy proves a proof-of-concept of adoptive cell therapy, and immunotherapy more generally, with its dramatic results in some otherwise terminal hematological malignancies. As pharmaceutical investment increases the pace of improvements has surprised most commentators. However, the cost (currently in the US of $475,000 (£340,000) per patient) and availability remain major barriers to routine use of these therapies currently.
The father of CAR-T therapy Prof. June discusses in more depth the future of CAR-T therapy
Title image: a group of killer T cells (green and red) surrounding a cancer cell (blue, center). The killer cell then uses special chemicals housed in vesicles (red) to destroy the cancer cell. Image from NIH, U.S.A. Image in Public Domain