In Conversation with Dr. Kadalmani Krishnan, CEO & Founder, Thrafford Lifescience
The global CAR T-cell therapy market is experiencing substantial growth, driven by increasing cancer incidence and advancements in cell therapy technology, with projections reaching USD 16.35 billion by 2032 and a CAGR of 12.5%.
In this context, we sit down with the founder and CEO of Thrafford Lifescience, a leader in the field of cellular therapies, to discuss the remarkable journey of CAR T-cell therapy and its profound impact on cancer treatment. As one of the pioneers in this innovative space, Thrafford Lifescience offers invaluable insights into the progress and challenges in CAR T-cell therapy, from its early conceptualization to its clinical applications.
The conversation covers key aspects of CAR T-cell therapies, including their success in hematologic cancers, the biological barriers they face in solid tumors, the promise of allogeneic (“off-the-shelf”) products, and innovations in manufacturing. With a focus on multi-target and armoured CAR T-cells, we explore the future of CAR T therapies and the breakthroughs that are paving the way for more effective, accessible treatments.
CAR T-cell therapy is often described as a paradigm shift in cancer treatment. How would you describe its journey from concept to clinical application, and what key milestones have defined its success so far?
The journey of CAR T-cell therapy from concept to clinical application is nothing short of revolutionary. It all began with the concept that we could genetically modify T cells to make them more effective at recognizing and attacking cancer cells. Early research, particularly in the 1990s, focused on engineering T cells with chimeric receptors that could target specific cancer antigens.
The first major milestone came with the discovery that T cells could be successfully modified to target B-cell malignancies, especially with the advent of CD19-targeted CAR T-cell therapies. Clinical trials began to show remarkable efficacy, particularly in hematologic malignancies like acute lymphoblastic leukemia (ALL) and large B-cell lymphoma. The approval of Kymriah (Tisagenlecleucel) by the FDA in 2017 for treating ALL, followed by Yescarta (Axicabtagene Ciloleucel) for large B-cell lymphoma, were watershed moments.
Currently, over 2,000 clinical trials are underway worldwide, underscoring the immense potential of CAR-T therapy. With a high likelihood of some of these molecules receiving approval in the near future, these breakthroughs are poised to usher in a transformative era in cancer treatment, solidifying CAR-T as a pivotal cornerstone of cancer immunotherapy.
So far, this therapy has shown remarkable efficacy in hematologic malignancies but faces significant hurdles in solid tumors. What, in your view, are the key biological barriers limiting its success in solid tumors, and how are current research efforts addressing these?
Solid tumors present unique challenges for CAR T-cell therapies, and I believe there are several key biological barriers at play. The tumor microenvironment in solid tumors is highly immunosuppressive, which makes it much harder for CAR T-cells to thrive and function. Factors like hypoxia, low pH, and the presence of immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells (MDSCs), essentially create a hostile environment for T cells.
Additionally, solid tumors often have a higher degree of antigen heterogeneity, have antigen loss or downregulation, meaning that CAR T-cells might not be able to target all the tumor cells effectively. The lack of ideal, tumor-specific antigens also makes it difficult to design CAR T-cells that can selectively target cancer cells without damaging healthy tissue.
Another challenge lies in developing innovative strategies for delivering CAR-T therapy to solid tumor sites. Whether targeting the brain, lungs, breast, or prostate, each of these areas may require distinct and tailored delivery methods to effectively combat the disease.
Research is addressing these challenges through several promising strategies, including engineering CAR T-cells to better penetrate the tumor microenvironment, using novel targets that are more specific to solid tumors, and combining CAR T-cells with checkpoint inhibitors, nanobodies, or other immune-modulating agents to improve their function and persistence in solid tumor settings.
Manufacturing complexities and high costs remain major barriers to the widespread adoption of CAR T-cell therapies. How do you see innovations in allogeneic (‘off-the-shelf’) CAR T products impacting accessibility and cost-effectiveness?
Allogeneic CAR T products are an exciting development in this space and have the potential to significantly address both cost and accessibility issues. The traditional autologous approach requires harvesting T-cells from the patient, modifying them, and then returning them, which is highly personalized but also time-consuming and expensive.
Allogeneic or “off-the-shelf” CAR T products, on the other hand, use T-cells from healthy donors that can be engineered and stored, ready for use in multiple patients. The ability to manufacture CAR T-cells in a more standardized, scalable manner holds the potential to drastically reduce production costs and treatment times. Innovations in gene-editing tools like CRISPR/Cas9 appear to have made it easier to modify these allogeneic T-cells, addressing concerns about immune rejection.
Researchers are exploring gene editing and immune modulation to reduce GVHD risk while maintaining T-cell effectiveness. Another hurdle is host rejection of donor cells, where the recipient’s immune system attacks the transplanted T-cells, limiting therapeutic success. Addressing donor compatibility and reducing variability in immune profiles is key to improving therapy outcomes. Additionally, variability in CAR T-cell products, based on donor immune differences, must be addressed to ensure consistent efficacy.
Good Manufacturing Practices (GMP) for raw materials are also crucial to meet regulatory standards, particularly in scaling up production for commercialization. Finally, proving the safety and efficacy of these therapies through clinical trials remains a critical step. Despite these challenges, allogeneic CAR T-cell therapy holds promise for improving accessibility, scalability, and affordability, reducing reliance on patient-specific cells. As manufacturing processes improve, these therapies may become more widely available, offering hope for broader patient populations in need of treatment.
By the virtue technological advantages allogenic is bound to increase the accessibility, scalability and affordability.
What are the critical requirements for setting up a facility to manufacture CAR T-cell therapies, and how does it differ from traditional drug manufacturing plants?
Setting up a CAR T-cell manufacturing facility is a highly complex process that requires specialized equipment, expertise, and strict regulatory compliance. One of the key differences from traditional drug manufacturing is the need for a sterile, controlled environment where patient-specific cells can be safely collected, modified, and expanded.
This requires facilities with advanced cleanroom standards, precise temperature and humidity control, and specialized labs for cell processing. Additionally, CAR T-cell manufacturing requires significant biological expertise, as it involves cell culture techniques, genetic engineering, and post-processing of cells, all of which must be carefully controlled to maintain cell integrity and function. In contrast, traditional drug manufacturing plants are focused on the production of chemical compounds or biologics, where processes like formulation and filling are less complex in terms of cell manipulation.
Setting up a facility to manufacture CAR T-cell therapies is fundamentally different from traditional drug manufacturing plants. In traditional manufacturing, the focus is on producing a tangible product, whereas in CAR T-cell therapy, the process itself is the product. For autologous CAR T-cell therapy, a centralized manufacturing model requires robust infrastructure to process patient samples efficiently and ship them back to clinicians with the shortest possible vein-to-vein time.
This rapid turnaround is critical to maintaining the effectiveness of the treatment outcome. Additionally, CAR T-cell manufacturing facilities cannot afford batch failures, as losing patient samples could result in the loss of a patient’s life. Another distinguishing feature is the need for flexibility in these facilities. As CAR T-cell technologies evolve rapidly—from autologous therapies to allogeneic approaches and even in vivo applications —manufacturing facilities must be able to quickly adapt and integrate new technologies. This requires a high degree of scalability and agility to accommodate advancements in the field, ensuring that the facility can keep pace with the changing landscape of CAR T-cell therapies.
To increase the accessibility – adopt scalable Point-of-Care Manufacturing and Processing (PoCMAP) platform. Initial success has been shown in the western world and Europe, where in the Ph-I clinical data is very encouraging and hence the regulators have approved the conduct of Phase II trial. Therefore, countries that require high throughput can try and adopt PoCMAP model.
Given the increasing focus on multi-target CARs and armored CARs, which specific modifications do you believe hold the greatest promise in improving durability and reducing antigen escape?
The development of multi-target CAR T-cells and armored CARs offers tremendous potential for improving the durability of responses and reducing antigen escape, two of the biggest challenges in CAR T-cell therapy. Multi-target CARs, which are engineered to target more than one antigen simultaneously, can help overcome antigen heterogeneity within tumors.
This approach increases the chances of effectively targeting all tumor cells, even if some lose expression of a single antigen. Armored CARs are another exciting development; these CAR T-cells are genetically modified to produce cytokines or other molecules that can enhance their persistence and function in the tumor microenvironment. For example, some armored CARs secrete interleukins like IL-12, which can boost T-cell activation and recruitment, while others may resist the immunosuppressive factors in solid tumors.
More basic research data demonstrating the undlerlying molecular and functional pathway, along with clinical data is being generated and appears promising with certain caveats. But given the disease state or unmet medical needs, these modifications hold promise in improving the overall efficacy of CAR T-cell therapies, particularly in overcoming challenges like antigen escape and poor persistence.
Cytokine release syndrome (CRS) and neurotoxicity are well-documented adverse events in CAR T-cell therapy. What are the latest strategies in clinical practice to mitigate these toxicities without compromising therapeutic efficacy?
Cytokine release syndrome (CRS) and neurotoxicity are among the most significant challenges associated with CAR T-cell therapy, but there have been promising advances in managing these toxicities. CRS occurs when CAR T-cells rapidly expand and release large amount of cytokines, which can lead to systemic inflammation. Neurotoxicity, often presenting as encephalopathy or cognitive dysfunction, can be a consequence of excessive immune activation.
The standard approach to managing these side effects includes the use of immune modulators like tocilizumab, an IL-6 receptor antagonist, which can mitigate the effects of CRS without compromising the efficacy of CAR T-cells. Another strategy is the careful monitoring and early intervention with corticosteroids in cases of neurotoxicity, although the goal is to avoid suppressing the CAR T-cells too much.
Additionally, researchers are working on engineering CAR T-cells to be more controllable, including the development of safety switches that can be activated to eliminate the T-cells in case of severe adverse events. These approaches aim to balance the therapeutic efficacy of CAR T-cells with the need for patient safety.
Apart from CRS & ICAN, current CAR-T therapies face challenges related to antigen escape and treatment resistance. One could deploy computational approach to design and optimize peptide-based CAR-T cell receptors with improved specificity and reduced toxicity. In-silico toxicity assessments by adopting advance technologies like quantum computation can aid identify minimal or off-target effects, ensuring safety in therapeutic applications. Such approaches can aid optimized receptor to maintain stable interactions despite antigenic variations, that can address a critical limitation of current CAR-T therapies. Such approach can provide a robust framework for designing next-generation CAR-T therapies with enhanced efficacy, reduced toxicity, and resilience against antigenic drift, paving the way for further experimental validation and clinical applications.
In a highly dynamic regulatory environment, how do you see regulatory frameworks evolving to keep pace with novel CAR T-cell designs and real-time clinical data from ongoing trials?
The regulatory landscape for CAR T-cell therapies is certainly evolving rapidly, and it will need to continue adapting as the technology advances. Regulatory agencies like the FDA and EMA have developed frameworks for reviewing CAR T-cell therapies, but the rapid pace of innovation, particularly with novel CAR T-cell designs and off-the-shelf products, will require more flexible and responsive regulatory pathways.
One of the key aspects of evolving regulation will be incorporating real-time clinical data and post-market surveillance into decision-making. We are seeing increasing focus on adaptive trial designs, where regulatory agencies are more open to continuous data collection and analysis during clinical trials, which can accelerate approval processes.
Additionally, as CAR T-cell therapies become more diverse and personalized, regulators will need to create tailored guidelines for each new approach, whether it’s multi-target CARs, armored CARs, or allogeneic therapies. The challenge will be to balance innovation with patient safety, ensuring that therapies meet rigorous standards without stifling progress.
Regulatory framework and guidelines will evolve as the technology is evolving and maturing. In this evolving ecosystem, many stakeholders including IBSC, IEC, RCGM, CDSCO, ICMR, manufacturing companies, CRO’s, CDMO’s, hospitals and the clinicians contribute to ensure patient accessibility and affordability to these transformative therapies. To keep pace with rapid developments in technology and massive amount of data being generated, there will be a need to not only to evolve regulatory guidelines but also upgrade polices for implementation and monitoring. Therefore, alignment of all the stakeholders must be the common goal of unmet medical need.
Personalized immunotherapy is becoming a key focus in oncology. How do you envision the integration of AI-driven patient selection and big data analytics in optimizing CAR T-cell therapy outcomes?
AI-driven patient selection and big data analytics are poised to play a critical role in optimizing CAR T-cell therapy outcomes. One of the challenges with CAR T-cell therapy is identifying the right patients who will benefit most from the treatment, as not all patients respond equally well. AI and machine learning can help analyze vast datasets to identify biomarkers that predict response to CAR T-cell therapy.
By combining genomic, proteomic, and clinical data, AI models can create more accurate profiles of patients, guiding clinicians in making personalized treatment decisions. Additionally, big data analytics can improve manufacturing efficiency by predicting optimal cell yields and identifying variables that may impact the success of therapy.
These technologies, when integrated into clinical practice, could help us better target CAR T-cell therapy to those most likely to benefit, while also providing insights into how we can refine the therapy itself to improve outcomes for broader patient populations.
AI can enable better clinical outcomes eg in Ph-I PK studies – prediction of functionalities and clinical outcome. Useful in dose escalation studies. Real-time integration into the conduct of the study will help in predicting SAE’s. Integration of AI right from the initial stage of clinical trial development plan will facilitate drafting protocols IB, SAP, MMP, PMP, SMP etc with explicit primary and secondary objectives. Further it may aid global harmonized dossier development for regulatory submissions and record keeping.
If you had to predict one game-changing breakthrough in CAR T-cell therapy over the next decade, what would it be, and why?
If I had to predict one game-changing breakthrough, it would likely be the successful development of off-the-shelf allogeneic CAR T-cell therapies that are both safe and effective across a broad range of cancers.
The ability to manufacture standardized CAR T-cells that can be readily used for any patient without the need for personalized production would revolutionize the accessibility and cost-effectiveness of CAR T-cell therapy. This would address one of the major barriers to widespread adoption. Coupled with advancements in multi-target CARs and gene-editing technologies like CRISPR, this breakthrough could significantly expand CAR T-cell applications, especially in solid tumours where the need is greatest.
Such an advancement would not only make CAR T-cell therapy more widely available and affordable but could also transform cancer care globally in ways that are currently hard to fully envision. Additionally, integrating manufacturing models like “PoCMAP” for allogeneic CAR T-cells, including in-vivo applications, could streamline the production process and bring therapies closer to patients faster.
Guest Bio
Dr. Kadalmani Krishnan, CEO of Thrafford Lifescience, is a visionary leader with over two decades in biotechnology and drug development. A Ph.D. from the University of Cambridge and post-doctoral research at Harvard Medical School fuel his transformative work in cell and gene therapies with mandate to making them accessible, scalable and affordable.
From leading India’s first GLP-RA biosimilar to securing $7M in grants, Dr. Krishnan has driven innovation at every stage—from R&D to regulatory approval. Now, at Thrafford, he’s spearheading PoCMAP, a breakthrough in cell therapy manufacturing. His expertise is shaping the next era of biopharma.
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