
T Cell Engineering: Crafting Cellular Warriors Against Cancer
by Dr. Mehdi Soleymani Goloujeh | October 11th, 2024
Introduction to the Challenge of Cancer
Cancer is one of the major global health issues, with its incidence steadily increasing and
mortality rates on the rise, affecting millions of people each year. In 2022, approximately 20
million new cancer cases and nearly 9.7 million cancer-related deaths were reported worldwide.
By 2050, cancer cases are projected to reach 35 million globally. In the US alone, more than 2
million new cancer cases are expected in 2024. These statistics underline the urgent need for
innovative and more effective cancer treatments.
Figure 1. Leading sites of new cancer cases and deaths in 2024
Traditional cancer therapies, including surgery, chemotherapy & radiotherapy, have been the
cornerstone of cancer therapy for decades; however, these approaches are extremely limited.
Unfortunately, chemotherapy and radiotherapy, both notoriously nonspecific treatments that
destroy cancer cells along with healthy ones, often cause significantly debilitating side effects
such as fatigue, nausea, hair loss as well as organ damage. Besides that, the cancer cells become
resistant to these treatments, making them ineffective for a period. This entails that new, more
specific, and long-lasting (and hopefully less toxic) treatments need to be investigated.
For instance, consider the case of a 45-year-old breast cancer patient who underwent multiple
rounds of chemotherapy. Initially, the treatment was effective, and her tumor shrank. However,
after several months, the cancer cells developed resistance, leading to a relapse. Each subsequent
treatment brought diminishing returns and increasingly severe side effects, significantly
impacting her quality of life. Such cases highlight the urgent need for more precise and enduring
therapeutic options.
The scope of novel cancer immunotherapies includes approaches involving the harnessing of T-
cell responses and T-cell engineering strategies. All these innovative approaches have the same
general concept, i.e., reprogramming the body’s immune system to target and kill cancer cells with high specificity without toxicity — this idea brings new hope for more efficient and less
noxious treatments. Among the most promising of these is T-cell engineering, a strategy that
involves modifying T-cells, a type of white blood cell, to better recognize and attack cancer cells.
In this article, we delve into the advancements and challenges of T-cell engineering, with insights
from Dr. Leonardo Ferreira, an expert in the field and Assistant Professor at the Medical
University of South Carolina (MUSC) and the Hollings Cancer Center.
The Science of T-Cell Engineering
T-cell engineering represents a is a groundbreaking approach in the fight against cancer. T-cells
play a key role in the immune system, responsible for identifying and eliminating infected or
malignant cells. However, cancer cells can evade immune detection through various
mechanisms, including the upregulated expression of inhibitory checkpoint proteins and the
establishment of an immunosuppressive microenvironment. T-cell engineering attempts to
overcome these hurdles by reprogramming T-cells to enhance their recognition ability and
destroy cancerous cells.
One of the most promising forms of T-cell engineering is CAR-T cell therapy. This approach
involves extracting T-cells from a patient, genetically modifying them to express Chimeric
Antigen Receptors (CARs) that specifically target cancer cells, and then putting these engineered
cells back into the patient. CARs are synthetic receptors that merge an antigen-recognition
domain with T-cell activation domains, empowering T-cells to recognize and eliminate cancer
cells more effectively.
The technology has been remarkably successful in treating certain types of blood cancers, such
as B-cell lymphomas and leukemias, where surface molecules like CD19 and BCMA serve as
effective targets. Another approach is T-cell receptor (TCR) engineering, which modifies T-cells
to enhance their natural ability to recognize cancer antigens presented by the body’s cells. Unlike
CAR-T cells, which target cell surface antigens, TCR-engineered T-cells can recognize
intracellular antigens presented on the cell surface by major histocompatibility complex (MHC)
molecules. This allows TCR-engineered T-cells to target a broader range of cancer-associated
antigens, including those derived from mutated proteins within the cancer cells.
Recent advancements in gene-editing technologies like CRISPR have further accelerated the
development of T-cell therapies, allowing for more precise and efficient modifications of T-cells.
These technologies enable researchers to edit T-cell genomes with high accuracy, enhancing their
specificity and reducing the risk of off-target effects. The potential of T-cell engineering is vast,
offering a targeted approach to cancer treatment that could overcome many limitations of
traditional therapies.
Dr. Ferreira highlighted the transformative impact of CAR-T cell technology on cancer
treatment. He noted that CAR-T cells, unlike traditional methods, can specifically target tumor-
associated antigens (TAAs) on cancer cells, making them particularly effective in liquid tumors
like B-cell lymphomas and leukemias. However, applying CAR-T technology to solid tumors
presents significant challenges. Solid tumors are not only more common but also more complex,
with a diverse range of antigens and a microenvironment that can inhibit T-cell activity. Factors
such as immunosuppressive cells, disorganized vasculature, and physical barriers within the
tumor microenvironment make it difficult for CAR-T cells to effectively reach and infiltrate solid
tumors.
Dr. Ferreira likened solid tumors to skilled immunologists, adept at evading immune responses,
which complicates the translation of successful liquid tumor treatments to solid tumor contexts. He discussed the evolving landscape of T-cell therapy, emphasizing that the development of TCR
and CAR engineering has often followed iterative cycles of discovery, application, and
reevaluation. For instance, the initial excitement around TCRs and tumor-infiltrating
lymphocytes (TILs) led to significant research, including studies that demonstrated the potential
of T-cells to target cancer cells effectively. The advent of synthetic biology and tools like
CRISPR shifted focus toward CAR-T cells, culminating in the first FDA-approved CAR-T cell
therapy in 2017. However, the limitations of CAR-T cells in treating solid tumors prompted a
renewed interest in TILs, as evidenced by the recent FDA approval of TIL therapy for
melanoma.
Innovative approaches such as TRUCK T-cells (T cells redirected for universal cytokine-
mediated killing), which combine the natural TCR mechanism with engineered components to
enhance functionality and durability, are also being explored. These developments underscore
the ongoing refinement of T-cell therapies, where both CAR and TCR technologies are not only
parallel tracks but also inform and enhance each other through continuous learning and
adaptation.
From Lab to Clinic: The Development Process
The development of T-cell engineering therapies is developed through a multi-step and highly
complex process, which is transversal to the whole spectrum of lifecycle, starting from discovery
to clinical integration. It begins with the discovery phase, in which researchers find and generate
working constructs for engineered T-cells Preclinical studies, where actual constructs undergo
testing in cell cultures and animal models to evaluate their safety as well as efficacy. Preclinical
studies are important to evaluate the therapeutic capacity of the engineered T-cells and pinpoint
any potential risks or side effects.
Once promising candidates are identified, the process moves into clinical trials, which are
conducted in multiple phases. Phase I trials are small-scale studies (usually with less than a
hundred subjects) that primarily focus on evaluating the safety and dosage of the therapy. If the
results are positive, the therapy progresses to Phase II trials, which involve a larger patient
population and aim to further assess efficacy and monitor side effects. Finally, Phase III trials are
large-scale studies that compare the new therapy to the current standard of care, providing the
data needed for regulatory approval.
Dr. Ferreira also explained the complexities of manufacturing CAR-T and TCR-engineered T-
cell therapies, highlighting challenges such as the availability and condition of T-cells, especially
in patients who have undergone extensive chemotherapy. He explained that CAR-T cell
manufacturing typically involves adding a new gene without altering the TCR, whereas TCR-
engineered T-cells require the elimination of endogenous TCR to prevent mispairing. Dr. Ferreira
also elaborated on the potential of allogeneic CAR-T cells, which use T-cells from healthy
donors instead of the patient’s own cells. While allogeneic CAR-T cells offer the advantage of
being readily available, they pose immune compatibility challenges, including the risk of GvHD
and host-versus-graft reactions. To mitigate these risks, genetic modifications such as knocking
out genes related to TCR and MHC expression are necessary.
Moreover, Dr. Ferreira touched on the potential risks associated with extensive cell manipulation,
including the introduction of unwanted mutations that could lead to serious complications, such
as CAR-T cell-derived lymphoma. As cell therapy technology advances, comprehensive
genomic screening and monitoring may become standard practices to ensure the safety of these
therapies before infusion into patients.
The transition from lab to clinic also involves scaling the production of engineered T-cells, a
process that must ensure consistency, quality, and scalability while adhering to stringent
regulatory standards. Recent advancements in automated manufacturing and bioprocessing
technologies are helping to address these challenges, enabling more efficient and cost-effective
production of T-cell therapies. Ensuring that engineered cells are produced consistently and
maintain their efficacy and safety is one of the significant hurdles in bringing T-cell therapies to
clinical application.
Clinical Trials and Treatment Successes
The success of T-cell engineering in clinical trials has been demonstrated by therapies such as
Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel), which have shown
remarkable results in treating certain blood cancers, including acute lymphoblastic leukemia
(ALL) and diffuse large B-cell lymphoma (DLBCL). These therapies have achieved remission
rates of up to 80% in some patient populations, offering new hope where traditional treatments
have failed.
Patient success stories, such as that of Emily Whitehead—the first pediatric patient to receive
CAR-T therapy for relapsed/refractory ALL—underscore the transformative potential of T-cell
engineering. After exhausting all other treatment options, Emily was treated with CAR-T cells
and achieved complete remission, inspiring many and highlighting the profound impact of these
therapies.
However, the outcomes of T-cell therapies can vary significantly among patients. Factors such as
the type of cancer, genetic makeup, and overall health of the patient can influence the
effectiveness of the treatment. Ongoing research aims to better understand these variables and
develop strategies to optimize outcomes for a broader range of patients. This research includes
the identification of biomarkers that can predict which patients are most likely to respond to T-
cell therapies, as well as efforts to enhance the persistence and durability of engineered T-cells
within the body.
Figure 2. Engineered T Cells Market Size
The potential market for engineered T-cell therapies is substantial. According to recent market
research, the global market for engineered T-cells is expected to reach approximately $349
billion by 2032, growing at a compound annual rate of 32.96%. Dr. Ferreira pointed out that
while CAR-T cells are currently approved primarily for liquid tumors, expanding these therapies to solid tumors would vastly increase the patient base, as solid tumors account for the majority of
cancer cases.
Commercializing Challenges
Commercializing T-cell therapies involves navigating several challenges, including regulatory
hurdles, production complexities, and high costs. The nature of CAR-T cell therapy as a “living
therapeutic” adds to these challenges. Unlike stable medications, CAR-T cells evolve from
extraction to reinfusion, complicating quality control and standardization due to their dynamic
nature. This complexity makes implementing consistent quality measures especially difficult.
Dr. Ferreira highlighted the high cost of CAR-T cell therapy, which currently stands at around
$400,000-$500,000 per treatment. This high cost poses significant barriers to widespread
adoption, particularly in healthcare systems with limited resources. To address these issues,
initiatives at academic centers, such as MUSC, are working to reduce costs through innovations
in manufacturing and production processes.
From a commercial standpoint, Dr. Ferreira noted significant bottlenecks in the production
process, particularly in securing sufficient quantities of GMP-grade viruses necessary for
modifying T-cells. This challenge is often compounded by delays at Contract Research
Organizations (CROs), which are critical in scaling and producing clinical reagents. CROs can
face backlogs that delay production timelines, further complicating the commercialization and
widespread deployment of CAR-T therapies.
Efforts to overcome these challenges include exploring alternative production methods, such as
non-viral gene delivery techniques, which could streamline the manufacturing process and
reduce costs. Additionally, innovative pricing strategies, such as outcome-based pricing and
installment payment plans, are being explored to make these therapies more affordable and
accessible to patients.
Challenges and Ethical Considerations
Despite their promise, T-cell therapies present several challenges and ethical considerations that
need to be addressed. One of the most significant complications is cytokine release syndrome
(CRS), a potentially life-threatening condition that can occur when the engineered T-cells release
large amounts of cytokines, leading to severe inflammation and organ damage. Managing CRS
and other side effects remains a critical area of research, with efforts focused on developing
strategies to predict, prevent, and treat these adverse events.
The high costs associated with T-cell therapies also pose an economic burden, limiting
accessibility for many patients. While efforts are underway to reduce costs through improved
manufacturing processes and economies of scale, achieving widespread affordability remains a
significant challenge. Expanding insurance coverage and government support will be crucial in
improving access to these life-saving treatments.
Ethical concerns around genetic modifications must also be considered. The long-term effects of
gene editing on human health are not yet fully understood, raising questions about safety and
consent. Regulatory bodies play a crucial role in ensuring that these therapies are developed and
implemented ethically, balancing innovation with patient safety. Dr. Ferreira noted that from a
regulatory perspective, the approval process for TCR and CAR-T cell therapies involves similar
scrutiny regarding gene and transgene safety, virus titers, and off-target effects. Both types of
therapies face challenges in defining target specificity and managing off-target risks,
emphasizing the need for thorough experimental validation.
Conclusion
The field is progressing swiftly, and the hopes are high for where T-cell engineering will go next.
But even with every increment, we are that much closer to a future in which we can target cancer
by the cell and less on old-school therapies that can be as destructive as they are effective.
Continued investment in research, a supportive regulatory environment, and a focus on reducing
costs will be key to realizing the full potential of T-cell therapies. As we advance, it is imperative
that these therapies not only extend lives but also enhance the quality of life for cancer patients
globally, embodying the true spirit of innovation in medical science.
Written by:
Dr. Mehdi Soleymani Goloujeh
Postdoctoral Fellow at UCSF Diabetes Center
LinkedIn Profile
Special Thanks to:
Dr. Leonardo M. R. Ferreira
Assistant Professor at the Medical University of South Carolina (MUSC) and the Hollings
Cancer Center
Ferreira Lab | LinkedIn Profile