By Utkarsh Acharya, DO, FACP
Dr. Acharya took amazing care of me when I had my CAR-T therapy in Seattle. He writes a more advanced article about why there is so much excitement about therapies that use living cells and speculates on where that therapy is headed. This article may be a bit intimidating for those new to the language of CAR-T and immunology. But even if you don’t understand every word, it is well worth the read. – Brian Koffman, MD
The use of adoptive cell transfer or cellular immunotherapy is founded on the premise that the body’s immune cells (T cells and Natural Killer (NK) cells) are innately capable of combating cancer. Early studies demonstrated tumor-infiltrating lymphocytes (TILs) were able to naturally identify and eradicate cancer cells. This principle has been reliably applied through the use of allogeneic hematopoietic stem cell transplantation (HSCT), the only curative cell-based treatment widely used in the management of various blood cancers. Allogeneic HSCT is performed through the infusion of rescue stem cells from a genetically “matched” donor to the patient after that recipient (often) receives intensive chemotherapy in a last-ditch attempt to kill off any remaining cancer cells. However, the potentially curative effects from allogeneic HSCT are not due to the stem cells but rather, achieved through donor-derived immune T cells that accompany the cellular product. The capability of the transplanted cellular product to eradicate cancer is thus, defined as the “graft versus tumor” effect. Unfortunately, this type of treatment may also result in unintentional damage to the recipient’s non-diseased tissues as the donor’s transplanted T cells recognize them as foreign – a phenomenon known as “graft versus host disease (GvHD)”. It is noteworthy, however, that while some GvHD is good as it confers complementary graft-versus-tumor effect, a lot can be potentially deadly and nullify the therapeutic intent of this approach. Therefore, the limitations with regard to identifying a suitable genetically “matched” stem cell donor, which influences the potential risk for severe GvHD associated with allogeneic HSCT, restrict universal eligibility and reflect the need for effective and tolerable immune cell-based strategies in our quest to combat cancer.
Autologous Chimeric Antigen Receptor T-Cell Therapy
Autologous chimeric antigen receptor (CAR) T cell therapy is one such approach that not only has the capacity to eradicate tumors through the T cell-mediated graft versus tumor effect present in allogeneic HSCT, but while sparing the complimentary risk of GvHD mentioned previously. Autologous CAR-T cells are a cancer patent’s own T cells that are genetically reprogramed to recognize specific surface protein(s) manifested on a cancer cell. While arguably overused, the word “unprecedented” does accurately reflect the profound impact this therapy has had on shifting the therapeutic landscape in cancer management for several hematologic malignancies. Specifically, CAR-T cells that have been engineered to target CD19 (a protein found on virtually all B-cell malignancies) have gained US regulatory approvals across several diseases including relapsed/refractory aggressive large B cell lymphoma, relapsed/refractory pediatric, and young adult acute lymphoblastic leukemia (ALL), and most recently, relapsed/refractory mantle cell lymphoma. These approvals are merited on the therapeutic potential of CAR-T cells to not only generate high response rates among heavily pretreated patients, whose diseases were otherwise deemed unsalvageable but also for their ability to induce deep and durable responses among responsive patients. The approval and availability of CAR-T cell therapy in these respective diseases has rapidly replaced chemotherapy for these indications and is being studied in earlier lines of therapy.
Treatment Considerations & Challenges with CAR-T Cell Therapy
While autologous CAR-T cells have inched us closer towards our finite goal to obliterate cancer, it would be naive to state that presently approved therapies are without limitations. Various considerations including patient and disease-related factors, long cellular manufacturing time, and concerns of treatment resistance/immune evasion pose just a few of the general therapeutic challenges that restrict the universal extension of CAR-T cells in the general management of cancer. The scientific principles that make CAR-T cell therapy so lucrative are based on their capacity to deliver personalized medicine for any given cancer. This is ultimately achieved through the identification of a protein that is exclusively found on cancer tissue in any given disease but spared on a respective patient’s healthy tissue. Among patients with B-cell malignancies, the CD19 protein is ideal as it is expressed universally on all B cells, and injury to normally expressing B cells does not pose fatal consequences. However, finding such a ubiquitously occurring and “expendable” target in other (non-B cell) cancers is more difficult. Secondly, the average manufacturing time to produce genetically modified immune cells may take several weeks, which poses a significant risk among patients with rapidly progressing diseases in dire need of immediate therapy. Lastly, while CAR T cells have been effective in generating robust disease responses in a large proportion of treated patients, there are patients who do not respond at all or ultimately lose their initial treatment response. The mechanisms for treatment failure largely stem from the body’s rejection of CAR-T cells (what we sometimes call loss of cellular persistence) and/or alteration in cancer’s biology, which no longer renders itself sensitive to the potency of manufactured CAR-T cells. One classical example of this is among CAR-T treated patients for B cell lymphoma/leukemia is through the loss of the target protein, CD19 – a phenomenon known as “CD19 antigen escape”. In supplement, and by no means in a mutually exclusive manner, cancers may create a hostile tumor environment intended to literally “exhaust” CAR T cells, thereby dampening their potency and effectiveness on attacking cancer cells.
Overcoming Challenges & The Future of Cellular Immunotherapy
Despite these noted challenges, multiple research efforts are underway to exploit the applicability of CAR-T cells and other cellular immunotherapies (e.g., TCR, NK cell, and TILs) across a wide span of cancer types. Active investigations are focused on identifying novel cancer targets to reduce the risk of unintended toxicity to healthy tissue for a truly personalized cellular immunotherapy approach. Additionally, multiple clinical trials are actively exploring the feasibility of “off the shelf” immune effector cell-based therapies in a broad array of cancers to overcome the logistical challenges of a long manufacturing time. Furthermore, there is a great emphasis on improving the responsiveness of CAR-T cells and reducing the mechanisms of resistance through combinatorial approaches (e.g., CAR-T cells plus other immune-enhancing drugs), designing advanced generation CAR-T cells that are more potent and persist longer (e.g., armored CARs), and the innovation of CAR-T cell designs that address multiple cancer-specific proteins to counteract “antigen escape” tactics as mentioned above.
While cautiously optimistic, cellular immunotherapy has a bright future with the potential to effectively replace conventional treatment approaches in a wide array of cancers. Our rapidly evolving understanding of the complex interplay between immune effector cells and cancer biology will not only facilitate the design of novel (and more potent) cellular therapies but will fill a critical unmet need to extend these potentially life-saving therapies to a broader range of patients. The proverbial race to the cure is in motion and all CARs are welcome!
TCR – T Cell Receptor
NK cells – Natural Killer Cells
TIL – Tumor-Infiltrating Lymphocytes
Dr. Acharya is an attending physician in the Immune Effector Cell Therapy Program at Dana-Farber Cancer Institute, Associate Physician at Brigham & Women’s Hospital, and an Instructor in Medicine at Harvard Medical School. He received his medical degree from Ohio University, completed his internal medicine residency at The Ohio State University, and hematology-oncology fellowship at the University of Arizona Cancer Center. Prior to joining Dana-Farber, Dr. Acharya was core cellular immunotherapy faculty at the Fred Hutchinson Cancer Research Center/University of Washington and attending physician at the Bezos Family Immunotherapy Clinic in Seattle, Washington. His clinical expertise is in adoptive cell transfer, namely CAR T-cell therapy, and his research interests focus on expanding and optimizing the utility/management of adoptive cellular transfer therapies across liquid and solid tumors.
Originally published in The CLL Society Tribune CAR-T Special Edition.
