A new era in cancer care

For decades, cancer treatment has relied on chemotherapy, radiation therapy and surgery. These therapeutic modalities have varying degrees of efficacy across different tumor types and often cause significant collateral damage. Chemotherapy indiscriminately targets rapidly dividing cells, resulting in systemic toxicity and immune suppression. 

Immunotherapy has transformed the field of oncology by harnessing the immune system’s innate ability to mount targeted attacks on cancer cells. This approach has the potential to minimize adverse effects and shorten recovery times, aligning with the principles of precision medicine.

Building on this foundation, cell and gene therapies (CGTs) take immunotherapy to the next level by reprogramming genetic blueprints and engineering immune cells to deliver highly personalized, possibly curative treatments. Together, these innovations could dramatically improve outcomes, with the potential to transform cancer into a more manageable condition — or even eliminate it. 

Driving immunotherapy’s success

Immunotherapy employs several mechanisms of action to enhance the immune system's ability to recognize and eliminate cancer cells with precision:

• Checkpoint inhibition: Agents such as PD-1/PD-L1 and CTLA-4 inhibitors release the immune system’s brakes, allowing T cells to recognize and attack tumors more effectively. These therapies have reshaped the treatment landscape for melanoma, non-small cell lung cancer and other malignancies.

• Adoptive cell therapy (ACT): ACT enhances the immune system's ability to target cancer through strategies like chimeric antigen T cell receptor (CAR-T) therapy and tumor-infiltrating lymphocytes (TILs). CAR-T therapy involves engineering T cells to recognize and destroy tumor cells, showing exceptional success in hematologic malignancies, including leukemia, lymphoma and multiple myeloma.

• Cytokine-based approaches: Cytokine-based therapies, particularly those targeting interleukin-2 (IL-2) and its receptor (IL-2R), amplify immune signaling pathways to enhance the immune system’s ability to recognize and eradicate cancer cells. These strategies focus on stimulating immune components, offering a promising avenue in the evolving landscape of cancer immunotherapy.

While immunotherapy has shown remarkable success in treating hematologic malignancies, its application in solid tumors presents unique challenges. Protective tumor microenvironments and mechanisms of immune evasion, such as immunosuppressive signaling and physical barriers, limit its effectiveness. Ongoing research aims to overcome these obstacles, solidifying immunotherapy's role as a foundational approach in the evolution of cancer treatment.

Why CGT could be the next frontier

Cell and gene therapies build upon immunotherapy by addressing cancer at its genetic and cellular origins, offering a more advanced and personalized approach. While immunotherapy enhances the immune system’s ability to fight cancer, CGT takes this a step further by engineering immune cells or modifying genetic material to directly target the root causes of cancer.

Gene therapy involves modifying or introducing genetic material into a patient’s cells to correct genetic mutations, enhance the immune system's ability to target cancer, or restore tumor-suppressor functions to combat cancer growth. Cell therapy uses reprogrammed or engineered immune cells, including CAR-T cells, to specifically recognize and eliminate cancer cells, enhancing the precision and effectiveness of the immune response.

CGT holds incredible potential with its ability to deliver highly personalized treatments and long-term efficacy, offering hope for transformative cancer care. Ongoing clinical advancements are exploring novel CAR-T constructs, such as dual-targeting effector cells, to overcome resistance mechanisms including downregulation of tumor antigens, which show promise in treating hematological malignancies.

Findings from a single-arm phase 2 trial suggest CAR-T cell therapy may be efficacious in the frontline management of aggressive B-cell lymphomas. An ongoing randomized phase 3 study is being conducted to compare the early incorporation of CAR-T cells with standard chemoimmunotherapy. These larger randomized trials are expected to provide crucial insights that could redefine how cancer is treated at earlier stages. 

Current barriers 

The scale-up problem 

Manufacturing CGTs presents significant challenges in scaling production, as these therapies rely on living cells as active ingredients, requiring strict sterility and consistency.

• Small-scale limitations: Current automated systems are designed for small-scale, single-patient batches.  Each system can occupy significant resources, such as a clean room, for several days per patient. This inefficiency, coupled with its labor-intensive nature, makes scaling up production to meet growing demand a considerable challenge.

• Cost and infrastructure barriers: The reliance on ISO 7 (grade B) clean rooms for manufacturing adds substantial costs. While these environments are critical for maintaining sterility, they significantly contribute to the already high price of therapies, limiting accessibility for patients.

• Supplier dependence: Many manufacturers depend on proprietary automated systems from a limited number of suppliers, creating vulnerabilities in supply chains. This lack of redundancy is at odds with the robust disaster recovery plans typical in traditional pharma manufacturing.

Addressing these challenges — through advancements in automation, decentralized manufacturing models, and regulatory facilitation — is essential to bringing CGTs to more patients.

The targeting puzzle

The foundation of any successful cell or gene therapy lies in selecting the right target. Effective therapies must balance specificity and durability to maximize efficacy while minimizing risks. Key characteristics of an ideal target include:

• Tumor-specific expression: Targets should be highly expressed on tumor cells but minimally expressed or absent from healthy tissue to avoid ‘on-target, off-tumor’ effects.

• Homogenous expression across tumor cells: To decrease the risk of residual disease or relapse, targets should be present on all tumor cells.

• Stability: Stable targets that remain bound within the tumor cell membrane are less likely to escape therapeutic intervention.

• Critical to tumor survival: Targeting essential pathways reduces the likelihood of cancer cells adapting or developing resistance through antigen downregulation.

The patient challenge

Patient-specific therapies, such as autologous CAR-T, depend heavily on the quality of pheresed cells, which can be compromised by prior treatments, particularly lymphotoxic chemotherapies. For example, agents such as bendamustine are particularly lymphotoxic, and their effects can persist for weeks to months after the final dose.

To mitigate this, a ‘washout period’ of certain therapies is often required before apheresis to optimize a patient’s T cell fitness. However, this waiting period can further delay the manufacturing process, exacerbating the time-sensitive nature of these therapies. The standard three-week manufacturing process, coupled with this additional delay, poses a significant risk for patients with aggressive malignancies, as clinical deterioration during this time may prevent treatment altogether.

Safety concerns further complicate the adoption of CGTs, with risks including severe immune-related adverse events such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infection, and prolonged cytopenias. These challenges highlight the need for improved precision in genetic editing, faster production timelines, and robust safety protocols to minimize risks.

Addressing the biggest CGT hurdles

Technological innovations are transforming the manufacturing of CGT products, providing scalable and cost-effective solutions while maintaining safety and quality standards. Some of these innovations include:

• Precision tools: Emerging tools such as CRISPR technology and advanced vector systems could enhance the precision and effectiveness of gene editing and delivery mechanisms.

• Automation and AI integration: Robotic systems combined with artificial intelligence are revolutionizing manufacturing processes. These systems ensure consistency by replicating human tasks with high precision, eliminating variability, and minimizing contamination risks. Fully closed systems supported by AI provide end-to-end aseptic processing, a critical requirement for these therapies where even minor errors can have major consequences.

• Decentralized manufacturing and mobile cell factories: Decentralized models bring production closer to patients, reducing risks of contamination and delays from transporting fragile cells. Hospital-based units and innovations like modular platforms integrate robotics and closed systems to ensure aseptic conditions and reduce variability. These technologies enhance scalability and accessibility, particularly for autologous therapies. Mobile cell factories, though in early stages, could further revolutionize point-of-care manufacturing.

• Leveraging biotech models: Established upstream processing techniques from biotechnology, such as mammalian cell culture, offer scalable frameworks for CGT production. Additionally, logistics models from radiopharmaceuticals provide valuable insights for managing the short shelf life of living cells and ensuring their timely delivery under stringent conditions.

These advancements are moving CGTs closer to widespread adoption, streamlining production and improving accessibility.

Evolving regulations

Regulatory agencies have made significant strides over the past decade to address the unique challenges posed by CGTs. Early regulatory frameworks, originally designed for sterile starting materials, struggled to accommodate the complexities of cell-based products, which often begin with contaminated biopsies. These gaps in guidance initially created obstacles to the development and manufacturing of these therapies.

Today, regulations have evolved to meet the demands of CGTs, providing clearer pathways for aseptic processing, sterility assurance and tailored oversight. Facilitation programs, such as orphan drug designations, scientific advice sessions and accelerated approval pathways, have significantly reduced barriers to clinical translation, particularly for therapies targeting rare and underserved conditions. Developers are increasingly engaging early and proactively with regulatory agencies to align development processes with compliance requirements and ensure smoother transitions from research to clinical application.

The future of cancer care

The future of cancer treatment lies in the convergence of innovation, personalization and collaboration. Immunotherapy and CGTs are transforming oncology, offering precision and the potential for curative breakthroughs. Yet, challenges remain: technological immaturity, scalability and patient variability continue to slow widespread adoption. Overcoming these barriers will require bold thinking, from leveraging AI and automation to adopting decentralized manufacturing models.

Could immunotherapy and CGT eventually replace chemotherapy and radiation in a subset of tumor types? It seems less a of question of if and more of when. As safety concerns are addressed and manufacturing processes evolve, these therapies could become first-line treatments, redefining cancer as a manageable or even curable condition.

For researchers, doctors and companies, the call to action is clear: Innovate with purpose and collaborate with urgency. Success will demand a multidisciplinary approach that bridges clinical, regulatory and technological expertise. The destination — a world where science and innovation converge to deliver precise, personalized treatments that offer the chance for a cure — is within reach. 

References

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ProPharma Group. 5 Challenges in the Development of Cell & Gene Therapy. ProPharma Group; 2023.

Donzelli, L., et al. Lymphocyte recovery after bendamustine therapy in patients with mantle cell lymphoma. Results of a retrospective analysis and prognostic impact in the CAR-T era. Ann Hematol. Aug. 2024. 

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