CAR-T Next Generation Immunotherapy: Better Targeting, New Approaches

The traditional treatments for cancer have been surgery, radiation and chemotherapy. Over the last quarter century, researchers have developed additional approaches mainly based on engaging the patient's immune system in some way to help fight their own cancer. They include: monoclonal antibodies (mAbs), small molecules as checkpoint inhibitors, gene therapy, vaccines and adoptive cell therapy (ACT).

ACT can be broken down into a number of sub-categories based on the type of technology involved. Chief among these are “adoptive transfer of autologous tumor-infiltrating lymphocytes (TIL), T-cells transduced with high-affinity T-cell receptors (TCR) against major melanosomal tumor antigens, and T cells transduced with chimeric antigen receptors (CAR) composed of hybrid immunoglobulin light chains with endo-domains of T-cell signaling molecules.” According to the National Cancer Institute, “the one [category] that has advanced the furthest in clinical development is called CAR T-cell therapy.”

To date, these therapies have been successful mainly against blood-born tumors (such as lymphomas and leukemias) in clinical trials, and gained FDA approval for use in certain children and young adults with a form of acute lymphocytic leukemia (ALL), a rapidly progressing and very deadly form of the disease. The CAR-T technology has also recently received FDA approval for the treatment of some types of large B-cell lymphomas, a form of an aggressive diffuse B-cell non-Hodgkin’s lymphoma.

“Tisagenlecleucel (Kymriah) was the first CAR T-cell product to be approved, and used for the treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). A few months later, axicabtagene ciloleucel (Yescarta) was approved for the treatment of adult relapsed/refractory diffuse large B-cell lymphoma (DLBCL) for which at least two prior therapies have failed,” Dr Marcela V. Maus told The ASCO Post in December 2017.

CAR-T cell treatment can, however, result in some serious side effects, not least of which is major toxicity. The immune cell activation can result in the release of too many cytokines, which can cause labored breathing, rapid pulse, high fevers and decreased blood flow to internal organs. In some cases, this condition (resulting from the “cytokine storm”, also known as Cytokine-Release Syndrome [CRS] may rapidly become very serious and life-threatening.

The future of immune-oncology therefore requires the development of modified TCR, TIL, CAR-T and/or other cell-based therapies including new immunological inventions that would provide both safe and effectivemethods to enhance, modify and allow the design and development of either gene-based modified cellular treatments and/or other therapies to be used as anti-cancer treatment(s). To be useful and available for many patients, these new therapies would have to be suitable for scale-up and be amenable to large-scale cGMP manufacture, including the development of the necessary analytical methods and tests to support the development of scalable, safe, effective and reproducible cellular or other therapies that can target solid tumors with high specificity.

The next-generation immune-oncology arsenal should therefore be aimed at developing better target-specific treatments for solid tumors that can respond (preferably in vivo) to the ever-changing tumor antigens, and which are designed to be safe and efficacious. Currently, there are many ongoing clinical trials that utilize CAR-T therapy being conducted by industry. The table^(*) below lists a number of trials utilizing CAR-T which are registered on the Clinicaltrials.gov website, aimed at solid tumors and being conducted at the National Institutes of Health (NIH).

*The information in the table was extracted from Clinicaltrials.gov website (the accuracy of this information is as reflected in that Website)

For instance, Maus stated, Dr. Martin Pulé of University College London is looking into a CAR based on a natural ligand rather than an antibody, and it would recognize two different antigens: B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI).

“Bluebird bio, in partnership with Scottish biotech TC Biopharm, is also targeting solid tumors with an improved version of CAR-T that uses a specific class of T cells known as gamma delta T cells.” This is expected to reduce toxicity.

Zelig Eshhar, pioneer of CAR-T technology, told The Scientist that he will be investigating these combinations of CAR-T cells and checkpoint inhibitors.

CEL-SCI of Vienna, Va., is nearing the end of a Phase 3 clinical study which is currently under way with Multikine (Leukocyte Interleukin, Injection), a patented investigational immunotherapy for treating solid tumors. Multikine is comprised of a mixture of pro-inflammatory cytokines released by immune cells that includes interleukins, interferons, chemokines and colony stimulating factors, all of which stimulate the body's healthy immune response. These cytokines have a specific effect on the interactions between immune cells and may have direct effects on tumor cells. Because its components have the potential to impart both active and passive immune activity, Multikine has the capability to be a combination immunotherapy and positioned to be a next-generation cancer immune-oncology therapy. Additionally, Multikine is administered locally in low doses around the tumor in order to reduce adverse effects and avoid the possibility of “cytokine storm.”

Seattle's Juno is now working on two second-generation CAR technologies that incorporate mechanisms to further amplify T-cell activation or to dampen it, in case of adverse reactions. (See “Safety concerns.”) These so-called “armored” chimeric antigen receptors are designed to combat the inhibitory tumor microenvironment by incorporating a signaling protein such as IL-12 (a cytokine), which stimulates T-cell activation and recruitment.

“Houston, Texas–based Bellicum Pharmaceuticals is working on refinements for next-generation CAR T-cell treatments. To better control antigen activation by its CAR T cells, for example, Bellicum is separating its dual costimulatory domain from the antigen-recognition domain, moving it onto a separate molecular switch that can be controlled by the small-molecule drug rimiducid. These T cells, known as GoCAR-Ts, can only be fully activated when they are exposed to both cancer cells and the drug.”

CAR-T has great promise but there are some significant problems that have yet to be overcome with this technology. CAR-T treatments in combination with other means of attacking tumor cells, and a wider range of approaches to ACT in general represent the second- and third-generation immune-oncology therapies being investigated to achieve better targeting of cancer cells with reduction in the toxicity profile of these treatments. These new therapies won't entirely replace the current standard-of-care cancer treatments—surgery, chemo and radiation—but they are inevitably poised to be the future of cancer treatment, while in the meantime helping make the current standard-of-care treatments more effective.

Eyal Talor is CEL-SCI’s Chief Scientific Officer. He is a clinical immunologist with over 24 years of hands-on management of clinical research and drug development for immunotherapy application, preclinical to Phase 3, in the biopharmaceutical industry. His expertise includes biopharmaceutical R&D and biologics product development, GMP (Good Manufacturing Practices) aseptic manufacture, Quality Control testing and the design and building of GMP manufacturing and testing facilities. Talor served as Director of Clinical Laboratories (certified by the State of Maryland) and has experience in the design of clinical trials (Phase 1-3) and GCP (Good Clinical Practices) requirements. His scientific area of expertise encompasses immune response assessment. In addition, he is the author of over 28 publications and has published a number of reviews on immune regulations in relation to clinical immunology.