For decades, the pillars of cancer treatment have been surgery, chemotherapy, and radiation. While these remain crucial, the landscape of cancer therapy has been transformed by new approaches in recent years.
The early 2000s witnessed the rise of targeted therapies like imatinib (Gleevec) and trastuzumab (Herceptin). These drugs selectively target cancer cells by honing in on specific molecular abnormalities. Today, numerous targeted therapies are standard treatments for various cancers.
Over the last decade, immunotherapy, treatments that harness the patient’s immune system to combat tumors, has emerged as the “fifth pillar” of cancer treatment. Immunotherapies have demonstrated remarkable ability to shrink or even eradicate tumors in some patients with advanced cancer, with responses lasting for years in a subset of individuals.
Immune checkpoint inhibitors are a prominent example, widely used to treat cancers like melanoma, lung, kidney, bladder, and lymphoma.
Another exciting form of immunotherapy is CAR T-cell therapy. Although not as broadly applied as checkpoint inhibitors, CAR T-cell therapy has shown the potential to eradicate advanced leukemias and lymphomas and maintain long-term cancer control.
Since 2017, the Food and Drug Administration (FDA) has approved six CAR T-cell therapies, all for blood cancers, including lymphomas, certain leukemias, and multiple myeloma.
Despite the excitement, long-term survival is achieved in less than half of treated patients. The high cost, exceeding $450,000 for the most recently approved therapy, has also drawn criticism.
Nevertheless, CAR T-cell therapy has become a significant advancement in cancer treatment, according to Steven Rosenberg, M.D., Ph.D., a pioneer in immunotherapy and CAR T-cell therapy at NCI’s Center for Cancer Research (CCR).
“CAR T cells are now widely accessible in the US and globally, becoming a standard treatment for aggressive lymphomas,” Dr. Rosenberg stated. “They are an integral part of modern medicine.”
CAR T-Cell Therapy: A “Living Drug” Approach
CAR T cells represent a “living drug” approach, as described by Renier J. Brentjens, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center, a leading figure in CAR T-cell therapy development.
The therapy relies on T cells, critical components of the immune system that orchestrate immune responses and directly eliminate infected cells.
Current CAR T-cell therapies are personalized for each patient. The process involves collecting T cells from the patient and modifying them in the lab to express chimeric antigen receptors (CARs) on their surface. CARs are engineered proteins that recognize and bind to specific antigens on cancer cells.
“These receptors are synthetic molecules, not naturally occurring,” explained Carl June, M.D., of the University of Pennsylvania Abramson Cancer Center, a pioneer in cellular therapy.
After the engineered T cells are expanded to millions in the laboratory, they are infused back into the patient. Ideally, these CAR T cells proliferate within the patient’s body and, guided by their CARs, target and destroy cancer cells bearing the specific antigen.
The FDA-approved CAR T-cell therapies target either CD19 or BCMA antigens found on B cells.
New Hope Where Options Were Limited
Initial CAR T-cell therapy development focused on acute lymphoblastic leukemia (ALL), the most common childhood cancer.
While intensive chemotherapy cures over 80% of children with B-cell ALL, effective treatments were lacking for patients whose cancer relapsed after chemotherapy or stem cell transplant.
However, in 2017, a new hope emerged with the FDA approval of tisagenlecleucel (Kymriah), the first CAR T-cell therapy. Approval was based on clinical trials demonstrating its ability to eradicate cancer in children with relapsed ALL.
Long-term outcomes for children treated with CAR T-cell therapy are now beginning to surface.
A study led by NCI researchers reported long-term follow-up data for children with relapsed ALL treated with CAR T cells in a clinical trial. Over half proceeded to potentially curative stem cell transplantation, and approximately 60% of these children were alive and cancer-free five years later, without disease-related complications.
“The progress with CAR T-cell therapy in children with ALL has been remarkable,” said Terry Fry, M.D., who has led CAR T-cell therapy clinical trials at NCI and Children’s Hospital Colorado. CAR T-cell therapy has rapidly become the standard of care for relapsed ALL in children due to its increased availability.
CD19-targeted CAR T cells also offer promise for adults and children with advanced aggressive lymphomas. Before CAR T cells, treatment options for these patients were severely limited, according to James Kochenderfer, M.D., of NCI’s Center for Cancer Research, who has conducted trials of CAR T-cell therapies in diffuse large B-cell lymphoma.
The outcomes in lymphoma have been “incredibly successful,” Dr. Kochenderfer noted, and CAR T cells have become a frequently used treatment for several lymphoma types.
Understanding and Managing CAR T-Cell Therapy Side Effects
Like all cancer treatments, CAR T-cell therapies can cause significant side effects, including B-cell aplasia and infections. Cytokine release syndrome (CRS) is a prominent and potentially serious side effect.
T cells release cytokines, chemical messengers that regulate immune responses. In CRS, infused CAR T cells release excessive cytokines into the bloodstream, leading to high fevers and dangerously low blood pressure. Severe CRS can be life-threatening.
Paradoxically, CRS is considered an “on-target” effect, indicating T cells are active. Patients with extensive cancer burden are more susceptible to severe CRS, Dr. Kochenderfer explained.
Mild CRS is often manageable with supportive care, including steroids. Experience with CAR T-cell therapy has improved the management of severe CRS.
Tocilizumab (Actemra), initially used for inflammatory conditions like juvenile arthritis, plays a key role in managing CRS. It blocks IL-6, a cytokine often secreted in large quantities by T cells and macrophages.
Neurological side effects, termed immune effector cell–associated neurotoxicity syndrome (ICANS), are another concern. These include confusion, seizures, and speech impairment. The exact cause of ICANS remains unclear.
While tocilizumab is effective for CRS, it does not seem to alleviate ICANS. Steroids, particularly dexamethasone, which penetrates the central nervous system better than other steroids, are the primary treatment for severe ICANS, according to Jennifer Brudno, M.D., an NCI CAR T-cell therapy trial investigator.
Strategies to prevent CRS and ICANS are under intense investigation, Dr. Brudno noted. Prophylactic use of tocilizumab and low-dose steroids is one approach. “The data so far are reassuring,” she said, although further research is needed.
Other ICANS treatments are being explored. Anakinra (Kineret), used for rheumatoid arthritis, may help prevent severe ICANS, according to smaller studies.
Modifying CARs themselves is another strategy to mitigate CRS and ICANS, Dr. Brudno explained.
A clinical trial of a “remodeled” CD-19-targeted CAR T cell developed at NCI showed significantly fewer severe neurological side effects in lymphoma patients compared to the original CAR design.
Expanding Targets: Solid Tumors and Beyond
CAR T-cell research is rapidly advancing, with hundreds of ongoing clinical trials. This expansion is fueled by the identification of new tumor antigens suitable for CAR T-cell targeting.
While CD19 and BCMA are currently the only antigens with FDA-approved CAR T-cell therapies, therapies targeting other blood cancer antigens, including multiple antigens simultaneously, are in development.
However, progress in using CAR T cells for solid tumors like brain, breast, or kidney cancer has been challenging. Identifying antigens specific to solid tumors but absent in healthy cells has proven difficult, Dr. Rosenberg noted.
The tumor microenvironment poses another hurdle. Physical barriers can prevent CAR T cells from reaching tumor cells. Immune-suppressing molecules within the microenvironment can also impair CAR T-cell function.
“Tumor heterogeneity” is a major challenge, according to Crystal Mackall, M.D., director of the Parker Institute for Cancer Immunotherapy at Stanford University.
Solid tumors of the same type can exhibit significant molecular diversity between patients and even within a single patient. Targetable antigens may be absent or insufficient for effective CAR T-cell function in some tumor cells.
Despite these challenges, researchers are actively seeking ways to apply CAR T cells to solid tumors.
One approach involves “armored” CAR T cells, engineered to overcome the immune-suppressive tumor environment by secreting cytokines and other molecules.
Other researchers are pursuing conventional CAR engineering approaches, targeting single surface antigens on cancer cells.
Following promising pre-clinical results, Dr. Mackall’s group at Stanford initiated an NCI-supported clinical trial of CAR T-cell therapies targeting B7-H3, a protein on solid tumors. Another trial is investigating a CAR T-cell therapy targeting GD2, a molecule on cancer cells, for children and young adults with DIPG, a uniformly fatal brain cancer.
The GD2 CAR T-cell trial has evolved significantly since its initial design, Dr. Mackall explained at the 2021 Society for Immunotherapy of Cancer annual meeting.
Initially, patients were to receive a single intravenous CAR T-cell infusion. However, animal model data led to trial modifications: patients responding to the initial infusion now receive additional smaller doses directly into the brain.
Multiple dosing has resulted in improved tumor responses and symptom reduction, she reported.
The research team also rapidly refined the GD2 CAR T cells and their manufacturing process to enhance efficacy and safety. This adaptability underscores the critical need for ongoing innovation in cellular therapies, Dr. Mackall emphasized.
“We are just beginning to scratch the surface of what we can achieve with CAR T-cell engineering,” she concluded. “Numerous next-generation approaches are addressing the limitations in solid tumors.”
Off-the-Shelf CAR T-Cell Therapies: CRISPR, Natural Killers, and mRNA
Researchers are also exploring alternative immune cell sources for CAR T-cell therapies, moving beyond patient-derived T cells to healthy donor cells. The goal is “off-the-shelf” CAR T-cell therapies, readily available without patient-specific manufacturing.
Current FDA-approved CAR T-cell therapies use viruses to deliver CAR-encoding genetic material into T cells. Off-the-shelf CAR T cells in clinical trials utilize gene-editing technologies like TALEN and CRISPR to induce CAR expression in donor T cells.
Other off-the-shelf approaches employ natural killer (NK) cells, a different type of immune cell. CAR NK cell therapies are being evaluated in early clinical trials.
Beyond cell source, the manufacturing location is also being reconsidered. Nanotechnology and mRNA-based approaches are being explored to enable CAR T-cell creation directly within the body.
CAR T-Cells: Moving Beyond Last-Resort Treatment?
CAR T-cell therapy is generally considered after cancer progresses through multiple prior treatments. However, this is beginning to shift.
Recent large clinical trials demonstrated CAR T-cell therapy’s superiority over standard treatment for non-Hodgkin lymphoma patients whose cancer relapsed after first-line chemotherapy.
These findings suggest CAR T-cell therapy may replace chemotherapy as the standard second-line treatment for these patients.
Dr. Fry suggests that earlier CAR T-cell therapy may be particularly beneficial for high-risk ALL children. Clinical trials are ongoing for children with ALL who show suboptimal responses to initial chemotherapy.
For responsive patients, “they could avoid two more years of chemotherapy,” Dr. Fry noted. “That’s an incredible prospect.”
