Ethan Carter
Amid widespread concerns about global issues, it’s crucial to recognize that we are currently experiencing a remarkable period of advancement in cancer treatment.
According to a report from the American Cancer Society published in January, the five-year survival rate for cancer patients in the U.S. has now reached an impressive 70%—the highest rate recorded to date. This achievement can be attributed to effective preventive screening initiatives and a significant reduction in major risk factors, such as smoking. medical professionals have developed the capability to treat and manage cancers that were previously deemed untreatable.
One of the most innovative developments in cancer treatment is chimeric antigen receptor T cell therapy, commonly referred to as CAR T cell therapy. This cutting-edge therapy utilizes T cells, typically harvested from the patient, which are genetically modified to express receptors that target specific antigens. This enables the T cells to recognize and eliminate cancer cells that bear those antigens.
Approved in the U.S. in 2017, CAR T cell therapy is now being employed to treat various blood cancers that have not responded to prior treatments. A considerable proportion of patients with these challenging cancers exhibit a positive response to CAR T therapy. While some cancer types show limited responsiveness, many patients facing otherwise terminal diagnoses have achieved lasting remission or even complete cures.
Numerous scientists contributed to the realization of CAR T cell therapy. Among the foremost pioneers is Renier Brentjens, the deputy director and chair of the Department of Medicine at the Roswell Park Comprehensive Cancer Center in Buffalo.
Brentjens played a pivotal role in early research demonstrating that CAR T therapy could effectively target blood cancers expressing the CD-19 antigen. He and his team at Memorial Sloan Kettering were also instrumental in coining the term CAR T. In 2024, he was honored, alongside three other scientists, with an award from the Warren Alpert Foundation for their significant contributions to the development of this therapy. Brentjens continues to work on advancing CAR T cells to target a broader range of cancers, particularly solid tumors.
I recently had the opportunity to discuss with Brentjens the current landscape of CAR T cell therapy, the substantial challenges it faces, and the future prospects of this innovative treatment. The following dialogue has been refined for clarity and grammatical accuracy.
Ed Cara, Gizmodo: What factors have led to CAR T being recognized as a breakthrough therapy for certain cancers? How does it differ from conventional chemotherapy and other treatment options?
Renier Brentjens: One of the most significant aspects of CAR T therapy is that it functions as a living drug. Immune cells are engineered to identify cancer cells outside the patient’s body and then reintroduced into the patient. Unlike conventional treatments, these engineered cells can persist and continue to target the tumor effectively. While many drugs can target cancer, CAR T cells have the advantage of being living entities that can adapt and persist over time.
Gizmodo: What challenges does CAR T therapy currently face?
Brentjens: Initially, there are economic and logistical challenges. The process is costly, as it involves harvesting the patient’s own cells, which are then modified over several weeks before reinfusion. This lengthy procedure contributes to the overall expense. The approved therapies are also quite expensive, presenting practical barriers.
Clinically, when a large population of engineered immune cells is infused, they become activated, leading to potential side effects. These effects were not observed during animal studies, but became evident in human patients, highlighting the need for careful clinical management.
There are also immunological challenges. The CAR T cells are designed to recognize a single protein, and while dual-targeting CAR T cells exist, they still do not address a critical issue: cancer cells may evade recognition by not expressing the intended target. This phenomenon, known as antigen escape, allows a subset of cancer cells to survive and proliferate even in the presence of CAR T cells, as those cells cannot recognize the tumor lacking the target antigen.
We have realized that tumors present substantial immunological complexity. Blood cancers have shown more success with CAR T therapy, particularly in B cell malignancies and multiple myelomas, as they represent more accessible targets for this technology.
In contrast, solid tumors, such as colon and breast cancers, are more intricate. These tumors consist of a diverse array of cells; only about half are cancer cells. The rest include fibroblasts that contribute to the tumor structure and immune cells that may suppress the immune response. This complexity poses challenges for the immune system’s ability to penetrate and effectively target the tumor.
The antigens expressed on solid tumors are not uniformly present across all cancer cells. This variability complicates the ability of CAR T cells to recognize and attack the tumor effectively.
Addressing these challenges is essential for achieving outcomes in solid tumors comparable to those observed in B cell cancers.
Gizmodo: What strategies are you currently exploring to overcome these limitations?
Brentjens: Our initial approach 30 years ago focused on creating immune cells that could target and eliminate cancer cells. Today, we understand that we must leverage the full potential of CAR T cells. These cells can locate tumors through their receptors and proliferate within the tumor environment, enabling us to introduce additional elements that can modify the tumor biology. One innovative strategy we are developing involves creating “armored” CAR T cells.
The concept is to equip CAR T cells not only with a receptor for recognizing and destroying tumor cells but also to add various functional components. For instance, we incorporate cytokines—proteins that enhance immune response—into the CAR T cells. Once these cells penetrate the hostile, immune-suppressive environment of a solid tumor, they can release cytokines that stimulate not just the CAR T cells but also activate other immune system components to attack the tumor more effectively.
This approach is not without risks. As previously mentioned, when the immune system engages the tumor, it can lead to fevers and cytokine release syndrome, which are already challenges with unarmored CAR T cells. we must proceed with caution as we introduce these advanced CAR T cells that produce their own pro-inflammatory cytokines. Many questions remain unanswered in this area.
Gizmodo: There are emerging strategies in CAR T research, such as developing “off-the-shelf” CAR T cells from donors or in vivo editing of a patient’s T cells. What are your thoughts on these innovative approaches?
Brentjens: These alternative approaches certainly hold promise for reducing time and costs. they are also laden with significant complexities.
The concept of off-the-shelf CAR T cells has been explored extensively, yet many clinical trials have not yielded superior results compared to using a patient’s own T cells. Currently, the most effective method for administering CAR T therapy remains the extraction, engineering in the lab, and reinfusion of the patient’s own T cells. While this doesn’t preclude other methods, starting with this established approach may be the best path toward achieving broader efficacy across various cancers.
While it is commendable that researchers are striving to make CAR T therapy more accessible and affordable, each proposed method has inherent limitations that have yet to be resolved. Compounding these limitations with the challenges of solid tumors and novel CAR T strategies could lead to significant hurdles.
Philosophically, I believe we should first establish the efficacy of autologous CAR T therapy, even if it is the most expensive option. Once we have a robust foundation, we can explore whether similar success can be achieved with more cost-effective methods.
Gizmodo: In summary, what do you envision for the short- and long-term future of CAR T cell therapy?
Brentjens: In the short term, improving CAR T cell construct design is essential.
Currently, FDA-approved CAR T therapies are based on receptor designs published over two decades ago. Given the extensive research conducted since then, it is surprising that our foundational work remains the standard today.
The volume of journal articles dedicated to next-generation CAR T cells is substantial. If someone had told me 20 years ago that our early designs would still dominate the field, I would have likened it to relying on outdated technology. In the near future, I hope to see the implementation of these next-generation constructs and an increase in survival and cure rates for blood cancers currently targeted by FDA-approved therapies.
There is also potential for improvements in production processes, which may help reduce costs and increase accessibility as more healthcare providers become equipped to administer these therapies.
Currently, CAR T therapy is typically utilized as a third- or fourth-line treatment. these therapies would be most effective as frontline treatments. By identifying patients unlikely to respond to chemotherapy and administering CAR T therapy earlier, we can enhance the health of T cells and minimize their exposure to chemotherapy.
While some may argue that CAR T therapy is more expensive, I contend that a single infusion capable of curing a disease presents significant long-term cost benefits, avoiding the extensive hospital stays and multiple cycles of chemotherapy often required with traditional treatments.
Shifting CAR T therapy closer to frontline treatment could yield transformative results.
The long-term success of CAR T cells will depend on our ability to adapt them for solid tumors. I am confident that the current designs for blood cancers will need substantial modifications to be effective against solid tumors. While there are numerous challenges ahead, the potential for innovation in the realm of immune cell therapies is vast. Working with living drugs offers unparalleled opportunities for creativity and advancement in cancer treatment.
Daniel Mercer
