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Daring To Learn From Failure: Insights On The Future Of Stem Cell Therapy

January 16th, 2025 | CAR T-cell | Cell Therapy | Hepatology | Oncology | Solid Tumors |
“Daring to Learn from Failure”: Insights from Dr. Robert Negrin on the future of Stem Cell Therapy

A Groundbreaking Therapy’s Origins

Stem cell therapy, particularly CAR T-cell therapy, has revolutionized the field of oncology, offering groundbreaking treatments for patients battling cancers that were previously deemed to be untreatable. This innovative therapy harnesses the body’s own immune cells and reprograms them to recognize and destroy cancer cells. The success of CAR T-cell therapy lies in its precision; it targets specific antigens on cancer cells, minimizing damage to other healthy tissues. As a result, where traditional treatments have failed, CAR T-cell therapy has shown remarkable efficacy in treating certain types of leukemia and lymphoma. With ongoing research and clinical trials, the potential applications of this therapy continue to expand, promising a future where cancer treatment is more personalized and effective, reducing the burden of disease for patients worldwide.[1]

CAR T-cell therapy history dates back several decades. The concept of using the body’s own immune cells to fight cancer began to take shape in the late 1980s and early 1990s. Researchers like Dr. Zelig Eshhar, at the Weizmann Institute of Science, were pivotal in developing the first chimeric antigen receptors or “CAR’s” – engineered proteins that allow T cells to target specific cancer cells. These early experiments laid the groundwork for what would become a revolutionary approach to cancer treatment, particularly in treating certain types of blood cancers.[2]

The process involves several key steps:[3]

StepDescription
1. CollectionLeukapheresis is performed to separate T cells from the patient’s blood.
2. Genetic ModificationCAR genes are introduced into the T cells using a viral vector.
3. ExpansionThe modified T cells are cultured and expanded in the lab to generate millions of CAR T cells.
4. PreconditioningThe patient undergoes chemotherapy to reduce the number of other immune cells.
5. InfusionThe CAR T cells are infused back into the patient’s bloodstream.
6. Activation and AttackCAR T cells bind to cancer cells, proliferate, and release cytotoxic substances to kill the cancer.

The first clinical trials for CAR T-cell therapy began in the early 2000’s, focusing primarily on blood cancers such as leukemia and lymphoma. The results were promising, showing significant remission rates in patients who had exhausted other treatment options[4]. Then in 2017, the FDA approved the first CAR T-cell therapy, tisagenlecleucel, for the treatment of certain types of leukemia.[5] This marked a major milestone in the field, opening the door for further research and development. Since then, the landscape of CAR T-cell therapy has evolved rapidly and significantly, with advancements aimed at enhancing benefits and expanding applicability.

CAR T-cell Therapy: Where Do We Go from Here?

Dr. Robert Negrin, a leading researcher in the field of cellular immunology was recently asked to provide insights into areas of advancement in the field, and to offer his take on the future direction of stem cell therapies. Dr. Negrin postulated three areas where significant progress is being made. He cited the expansion of cell therapy into earlier lines of treatment, the ongoing effort to overcome barriers in treating solid tumors, and the possibility of generating CAR T-cells directly within a patient’s own body. Each of these possibilities not only illustrate the vast potential of cell therapies, but also reflect the innovative spirit and perseverance of the researchers who are working to revolutionize cancer treatment.

  1. Expanding CAR T-Cell Therapy into Earlier Treatment Lines

Initially, cell therapy treatments such as CAR T-cell therapy were reserved for patients with advanced-stage cancers, often as a last-resort option after traditional therapies had failed. In the past few years, however, these therapies have shown such promising results that they are now being considered in earlier stages of cancer treatment.[6]

Dr. Negrin emphasizes the importance of this shift, noting that cell therapies are “moving up in line,” and explaining that “all these therapies start in more advanced-stage patients, but it’s really important to anticipate what the results are going to be, and then move them up into earlier lines of therapy… there is a lot going on in both B cell lymphoma and multiple myeloma.”

This transition is being driven by advancements in both risk stratification and diagnostic tools, allowing clinicians to identify patients who may benefit most from early intervention. New assays and improved methods of measuring tumor burden, for instance, are enabling doctors to detect and address aggressive cancers sooner. Dr. Negrin points to the importance of identifying high-risk patients who are likely to relapse under standard therapies. By intervening earlier with cell therapies, clinicians hope to improve long-term outcomes and potentially reduce the risk of recurrence. He notes that “developing better assays to measure tumor burden and in particular minimal residual disease” can help identify patients in remission by conventional standards, but who may still be at risk of relapse.”

An illustrative example of the integration of CAR T-cell therapy into earlier treatment lines can be seen in hematological malignancies. In patients with relapsed large B-cell lymphoma, CAR T-cell therapy has been proven to provide long-term remission, even in those who previously exhibited no response to chemotherapy. By refining risk stratification methodologies, researchers are increasingly able to detect patients with concealed residual disease who may still be at risk despite appearing in remission.

Dr. Negrin explains that moving cell therapies into earlier treatment lines not only has the potential to increase survival rates but also to minimize the suffering of patients who would otherwise endure multiple rounds of less effective treatments.

“Success in treating high-risk blood cancers like B-cell lymphoma and multiple myeloma with CAR T-cell therapy is paving the way for more proactive treatment approaches. However, even with these advancements, challenges remain, particularly in assessing which patients can handle the intense side effects associated with CAR T-cell therapies. The hope is that as research continues, clinicians will be able to better predict patient outcomes and refine treatment protocols to maximize benefits and minimize risks.”

  1. Addressing Immunological Challenges in Solid Tumors

While CAR T-cell therapy has seen substantial success in blood cancers, replicating these results in solid tumors remains a formidable challenge. Solid tumors differ significantly from blood cancers in their biological composition, with many housed in complex, immunosuppressive micro-environments that actively hinder immune responses. Dr. Negrin discusses the difficulties posed by the tumor microenvironment, remarking, “It’s still not fully understood as to why we have had so much more success in blood cancers than in other settings. People inevitably gravitate towards the concept of the tumor microenvironment as a barrier in solid tumors… that there is something inherently immunosuppressive in the tumor microenvironment – but how to disrupt that, has been elusive to researchers thus far.”

The tumor microenvironment essentially acts as a shield, making it difficult for immune cells, including modified CAR T-cells, to penetrate and sustain an attack on the tumor cells. Researchers believe that elements within this microenvironment create a hostile setting for immune cells by releasing immunosuppressive signals and creating physical barriers that prevent immune cell infiltration. This has forced scientists to rethink their approach and to develop new strategies aimed at enhancing the resilience and efficacy of CAR T-cells.[7]

One promising avenue of research involves engineering CAR T-cells to target multiple antigens, rather than a single one, which could help minimize the risk of tumor cells escaping therapy by mutating or shedding a particular antigen. By targeting multiple sites on the tumor, scientists hope to create a more comprehensive attack on the cancer cells.

“One of the key questions in the field,” Dr. Negrin explains, “is, does this also induce a broader immune response? Namely that in some patients antigen loss is the reason for failure. So, can you target more than one thing? Can you have two targets or three targets, and with that reduce the risk of a so-called antigen escape? This is another big area that researchers are focusing on, how do we get away from these very individualistic treatment concepts?”

Researchers are also investigating ways to break down or bypass the barriers of the tumor microenvironment. The development of therapies that modulate the immune system to counteract the immunosuppressive effects of the tumor microenvironment is one area of intense study. While the complexities of solid tumors continue to pose challenges, the insights gained from blood cancer treatments offer a valuable foundation for overcoming these hurdles. As scientists gain a deeper understanding of the mechanisms at play in solid tumors, they are hopeful that similar breakthroughs to those seen in blood cancers may soon be within reach.[8]                                                                       

  1. The Future of In-Body CAR T-Cell Production

One of the most revolutionary and ambitious objectives in CAR T-cell therapy is the development of methods to generate CAR T-cells directly within the patient’s body. Currently, CAR T-cell production involves extracting a patient’s T-cells, modifying them in a laboratory setting, and subsequently re-infusing them into the patient. This process is resource-intensive, time-consuming, and costly, making it challenging to scale.

Dr. Negrin envisions a future where CAR T-cells can be generated within a patient’s own body. Doing this will eliminate the need for external manipulation. Dr. Negrin states, “The next generation will be incredibly exciting – can you make these CAR T-cells in the patient’s themselves, without taking them out of the body?”

Recent technological advancements are bringing this vision closer to reality. Utilizing gene transfer techniques, such as viral vectors or CRISPR (a precise gene-editing tool), scientists are exploring methods to deliver genetic instructions directly to T-cells within the patient’s bloodstream.[9] By modifying T-cells in vivo, researchers aim to streamline CAR T-cell therapy, making it more accessible and reducing the logistical burdens associated with the current process. McKinsey & Company’s analysis on CAR T-cell therapy suggests that in-body CAR T-cell production could not only reduce costs but also enhance accessibility for patients in need of rapid treatment.[10]

The potential benefits of in-body CAR T-cell production are substantial, as it would facilitate a more efficient and scalable approach to cell therapy. By eliminating the need for an external laboratory process, clinicians could reduce the time between diagnosis and treatment, potentially increasing survival rates for aggressive cancers that require immediate intervention.

However, in-body CAR T-cell production also necessitates advancements in gene transfer technologies and precise delivery mechanisms to ensure that only the targeted cells are modified, and these advancements are still in the research stage. The promise of in-body CAR T-cell generation represents a significant milestone in cell therapy’s evolution.

An Opportunity to be the First

As stem cell therapy advances, so too does the hope for effective cancer treatments that are accessible to a broader patient population. The future of CAR T-cell therapy brims with promise, reflecting the unwavering dedication of researchers and clinicians alike to push the boundaries of contemporary medicine. Forward thinking researchers supported by unbiased CRO’s have an opportunity to be first in line for these game changing breakthroughs.

Dr. Negrin encapsulates the difficult task that lies ahead, “Learning from failure is crucial, and requires incorporating ancillary sciences. It’s essential to consider the questions we aim to address and integrate them into our trials. This approach is fundamental. And though it can be costly, it provides trialist’s with an opportunity to learn and adjust our treatments that hopefully will be even more effective.”

Negrin

Dr. Negrin

Robert S. Negrin, MD is a Professor of Medicine and former Chief of the Division of Blood and Marrow Transplantation at Stanford University from 2000-2020. He received his undergraduate degree from the University of California at Berkeley and MD from Harvard University. He trained in medicine and hematology at Stanford University and joined the faculty in 1990. His research work has focused on cellular immunology developing a more fundamental understanding of complex biological reactions such as graft versus host and graft vs tumor reactions in animal models and in the clinic. He has received many awards including the Doris Duke Distinguished Clinical Scientist Award and is a member of the Association of American Physicians. He was previously the President of the International Society of Cellular Therapy and the American Society of Blood and Marrow Transplantation. He served as an Associate Editor of the journal Blood and is the founding editor of Blood Advances. He is the Vice President of the American Society of Hematology with successive terms of President Elect in 2025 and President in 2026.
[1] Stem Cell Research & Therapy Referencing Guide
[2] Current advances and challenges in CAR T-Cell therapy for solid tumors https://ehoonline.biomedcentral.com/articles/10.1186/s40164-023-00373-7
[3] CAR T Cells and T-Cell Therapies for Cancer – JAMA Network. https://jamanetwork.com/journals/jama/fullarticle/2825799.
[4] CAR T cell – Wikipedia. https://en.wikipedia.org/wiki/CAR_T_cell
[5] T cells: A 60-year tale – Nature. https://www.nature.com/articles/d42473-022-00433-2.
[6] (1) CAR T Cells and T-Cell Therapies for Cancer – JAMA Network. https://jamanetwork.com/journals/jama/fullarticle/2825799
[7] Reshaping the tumor immune microenvironment to improve CAR-T cell-based …. https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02079-8
[8] Reshaping the tumor immune microenvironment to improve CAR-T cell-based …. https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02079-8
[9] The next-generation CAR-T therapy landscape – Nature. https://www.nature.com/articles/d41573-023-00140-7
[10] https://www.mckinsey.com/industries/life-sciences/how-we-help-clients/digital-capability-center-cell-and-gene-therapy