Movers and SHAKERS
CAR-T and the Possibility of Cancer Treatment, Part 1
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Chimeric Antigen Receptor T cell therapy (CAR-T) is a gene therapy designed to harness the potency of antibodies and T-lymphocytes into one single medicine for the treatment of cancer. CAR-T therapy could be viewed as a “living anti-cancer drug” as the medicine itself consists of a living cell, which is genetically engineered to find and destroy cancer cells. Dr. Carl H. June pioneered this technology at the University of Pennsylvania, where the first tests were conducted in cancer patients in 2010. Seven years later, the U.S. Food & Drug Administration (FDA) approved this novel gene therapy for the treatment of patients suffering from “B-cell precursor acute lymphoblastic leukemia” (ALL), a type of blood cancer known to be the most common malignant growth in children.
Thus far, anti-cancer antibodies have been one of the most successful drug classes for the treatment of cancer patients. Antibody drugs such as Roche’s Avastin, Herceptin and Rituxan have prolonged survival of many cancer patients. Another class of medicines, known as T-infiltrating lymphocytes (TILs), has been shown to be effective as an anti-cancer treatment. Given the relative success of both therapeutic strategies, the question is, how do you combine both treatments into one potent anti-cancer drug?
CAR-T represents the solution to this riddle. CAR-T consists of two main components: 1) the tumor associated antigen (TAA) domain of an anti-cancer antibody (scFV) linked through a spacer/transmembrane region to 2) the cytoplasmic domain of the receptor of a cancer-killing T lymphocyte. The new anti-cancer drug, CAR-T, is a genetically engineered T-lymphocyte expressing a chimeric T cell receptor on its surface (Figure 1). This chimera consists of the binding domain of the antibody (external domain protruding from the cell surface), fused to the signaling portion CD3 of the T cell receptor (internal domain facing the cellular cytoplasm).
Figure 1 – Structure of a CAR-T construct. The left panel depicts a CAR-T medicine (first generation), whereas the right panel depicts the natural T cell receptor, TCR. In the CAR-T construct (left panel), the binding domain (light blue/purple) of an anti-cancer antibody (scFV) replaces the alpha/beta chain portion (green/red) of the natural TCR (right panel). The transmembrane and cytoplasmic components of CAR-T and TCR, including CD3 domain, are depicted in blue.
Source – Oncotarget 2015, 8(52)90521-90531 ?
To generate a CAR-T drug, five main steps are required (Figure 2):
- blood from the patient is extracted
- T-lymphocytes are purified from extracted blood, and subsequently genetically modified to express the CAR chimeric receptor
- CAR-T cells are grown in vitro (ex vivo)
- Once CAR-T cells are grown to reach a therapeutic dose, they are injected back into the patient
- Injected CAR-T cells are engineered to find and kill cancer cells
Source – The University of Texas Southwestern Medical Center
Success of Gilead and Novartis bodes well for the future of CAR-T approach
In 2017, the U.S. Food and Drug Administration (FDA) approved two CAR-T therapies for the treatment of blood cancers. Novartis Kymriah and Gilead’s Yescarta were approved by the agency for the treatment of pediatric acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL), respectively. Patients who have not responded to, or who have relapsed following at least two other conventional treatments, are eligible for CAR-T therapy. The success of these two gene therapies in human clinical trials, followed by FDA endorsement and commercialization clearance have led to heightened enthusiasm on the potential for this cancer treatment. In clinical trials, CAR-T therapy demonstrated a 90% complete remission rate in B-cell acute lymphoblastic leukemia patients (Complete remission corresponds to the disappearance of all signs of cancer in response to treatment. However, it does not mean the cancer is cured).Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL in adults. Gilead’s Yescarta is approved for the treatment of adult patients suffering from various types of NHL including DLBCL, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. In human clinical trials, patients treated with Yescarta showed a complete remission rate of 51 percent. Although not a reality yet, industry experts believe the positive experience seen with CAR-T drugs for the treatment of blood cancers will translate to similar success in solid tumors.
CAR-T Complexity and High Prices Remain as Significant Challenges
Developing an effective living therapy for the treatment of cancer will not come without significant challenges. To recreate the immunological synapse in cancer patients is difficult, due to the complexity of the interaction of T lymphocytes with cancer cells. Giving that CAR-T cells are alive, they will respond to inhibitory signals from the tumor microenvironment, which could potentially inhibit their function and shut down the killing capacity of these cells. This has been the case with CAR-T drugs developed for the treatment of solid tumors such as lung cancer, breast and prostate cancers. Solid tumors present many barriers to CAR-T cells. The solid mass of a primary tumor creates physical barriers hindering penetration by CAR-T cells. Cancer cells populating a solid tumor can themselves diminish expression of tumor associated antigens (TAAs) on their surfaces, making the target elusive to CAR-T cells. Cancer cells heterogeneity, combined with the release of inhibitory cytokines, have been shown to create a prohibitive environment for CAR-T cells.
At present, CAR-T treatments are very expensive, with Novartis’s Kymriah and Gilead’s Yescarta carrying price tags of $475,000 and $373,000, respectively, just for a one-time treatment per patient. In the opinion of industry experts, the price of CAR-T gene therapy would have to come down before significant market penetration is achieved in oncology markets. At present, another obstacle to widespread adoption of CAR-T therapies is related to the safety of these drugs. CAR-T therapy is often associated with neurotoxicity and cytokine storms (abnormally high levels of pro-inflammatory cytokines), which could be fatal in some treated patients.
How to Engineer Better CAR-Ts for the Treatment of Cancer
The fact that CAR-T drugs are “living cancer treatments” offers the possibility to modulate their functions in vivo. Scientists have designed different approaches to diminish neurotoxicity of CAR-T drugs. Chimeric receptors in CAR-T constructs could be designed to be turned on and off, depending on specific patient needs. Additional domains could be added to the cytoplasmic portion of the chimeric receptor to boost the killing functions of CAR-T cells, increase their longevity, duration of immunological activity, avoid exhaustion, and overcome inhibitory signals from the tumor microenvironment. These improvements are of paramount importance when treating solid tumors with CAR-Ts. Furthermore, CAR-T constructs could be engineered to simultaneously target multiple tumor antigens, and to express specific cytokines which could engage the host immune system, thus amplifying the anti-tumor immune response and improving the treatment’s efficacy.
Significant efforts are being made to develop “off-the-shelf” CAR-T cells, which could lower price tags and simplify the manufacturing process for these complex anti-cancer medicines. Better selection of T cells subsets to prepare the CAR-T product will potentially improve durability and efficacy of the treatment (stem T cells with proliferative/differentiation potential, rather than effector T cells, are better suited as a source to manufacture CAR-T medicines). The advent of gene-editing technologies such as CRISPR allows for more efficient genetic manipulation and engineering of CAR-T constructs. Although these approaches are currently being evaluated in preclinical models and human clinical trials, the consensus view is that there is still ample margin for improvement in CAR-T product design for the treatment of cancer. For a deeper dive into innovations in CAR-T space by emerging industry leaders in read Part 2 of this article series here.
Programming CAR-T cells to kill cancer. Nature Biomedical Engineering 2018, Vol 2, June 2018, p377-391
Switching on the green light for chimeric antigen receptor T-cell therapy. Clinical & Translational Immunology 2019, Vol 8, e1046
CAR-T with License to Kill Solid Tumors in Search of a Winning Strategy. International Journal of Molecular Sciences 2019, Vol 20, p1903
Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: challenges and opportunities. Oncotarget 2015, Vol 8(52), p90521-90531