The Promise of Chimeric Antigen Receptor (CAR) T-Cell Therapies for Cancer Treatment

The Promise of Chimeric Antigen Receptor (CAR) T-Cell Therapies for Cancer Treatment

By Andres Lorente

Cancer is a collection of related diseases characterized by the abnormal proliferation of cells and their spreading to surrounding or distant tissues. From a medical perspective, cancer is a very challenging disease because it is caused by the patient’s cells going haywire. This fact further complicates treatment, as the patient’s immune system typically does not mount strong reactions against cancer cells because they are identified as self.

At initial developmental stages, cancers are tough to detect. As mutations accumulate, cancers become more and more aggressive and, unfortunately, it is at these later stages that most cancers are diagnosed.

One of the promising new approaches to fighting cancer is through immunotherapy. Immunotherapy stimulates the body’s immune system in a way that enables these cells to recognize and attack cancerous cells. One of the two most significant cancer immunotherapy approaches the chimeric antigen receptor (CAR) T-cell, a cell-based therapy.

How Is the CAR T-Cell Therapy Performed?

The CAR T-cell therapy first involves obtaining T-cells from the patient (allogeneic) or a close histocompatible donor (allogeneic). These cells are then genetically engineered to express chimeric receptors that recognize a specific cancer marker (antigen). The engineered CAR T-cells are multiplied in vitro for immediate use and long term storage for subsequent use. Finally, the cells are transfused into the patient.

Once CAR T-cells detect cancer cells, the internal portion of the chimeric receptor signals the T-cells to proliferate, release immune system modulating chemicals called cytokines, and promote the death of the detected cancer cells.

What Are the Advantages of CAR T-Cell Therapies?

The two greatest benefits of this therapy are that the chimeric receptors ensure that this therapy is a targeted therapy, and most importantly –since CAR T-cells are “live cells”– they are expected to amplify in the patient to establish immune memory, provide continuous surveillance to treat local and metastatic lesions, and keep the targeted cancer cell population in check. CAR T-cell expansion inside the patient, however, has proven to be surprisingly challenging in most cases.

Will CAR T-Cell Therapies Be the Next Disruptor in Cancer Treatment?

CAR-T cell therapies that target cancer cells expressing the surface marker CD19 have been very successful in the treatment of hematologic malignancies such as B-cell acute lymphoblastic leukemia. Moreover, this approach has proven to be reasonably scalable and not to be cost-prohibitive. Together, this prompted testing CAR T-cell therapy approaches to treat other cancers using a wide variety of cancer antigens and a wide range of strategies to generate highly responsive chimeric receptors.

The impact of CAR-T-cells for cancer treatment cannot be overstated. This is a disruptive approach with a lot of promise. Within ten years, it has gone from a few failed trials to being one of the most successful cancer therapies. As of July 3rd, 2016 there were 150 CAR T-cell clinical trials reported at ClinicalTrials.gov, 19 for solid tumors and 131 for hematological malignancies such as leukemia, lymphoma, and myeloma.

Three big caveats of CAR T-cell therapies are that their effectiveness depends on cancer cells expressing unique antigens, a feature typical of aggressive cancers, that some of these antigens will cause off tumor cell targeting leading to undesired side-effects, and that this approach has not been very successful for the treatment of solid (non-hematologic) tumors.

Why Cell-Based Therapies Are Less Effective For Solid Tumors?

Solid tumors present several extra challenges compared to hematologic cancers. They are surrounded by an immunosuppressive microenvironment that dampens the immune system, and they typically are genetically heterogeneous populations where some cells escape therapy because they are no longer affected by the treatment and because of changes in the surface molecule repertoire (e.g. antigen loss).

The future of the use of this approach to cure cancer relies on several factors:

    1. Identification of new cancer-specific antigens to target more cancers and –more specifically– also to minimize side-effects,
    2. Design of safe and tightly regulated hyper-responsive chimeric antigen receptors,
    3. Improvement of T-cell harvesting, engineering, and in vitro expansion protocols,
    4. Increasing engineered T-cell safety and likelihood of in vivo cell expansion upon stimulation,
    5. Generation of standard off-the-shelf CAR T-cells to make therapies available to all patients while avoiding tissue rejection and expediting treatments (ongoing by Cellectis),
    6. Effective combination with other approaches to achieve successful and stable remission, and
    7. Ensuring all procedures and improvements are scalable.

Conclusion

The impact of this research is enormous. A cure for cancer is a tall order and will require much more research and will likely require the use of different combinations of therapeutic approaches. The use of CAR-T-cells and monoclonal antibodies against PD-1 or its receptors PD-L1 or PD-L2 to bypass the immune checkpoint (not discussed here) represents significant advancements in the fight against cancer.

Image courtesy of freerangestock.com

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