Transforming Lymphoma Treatment with Advanced Bioprocessing

Lymphoma Types and Classifications

Lymphoma is a type of blood cancer that originates in lymphocytes, a type of white blood cell found primarily in the lymph nodes, spleen, thymus, and bone marrow. The uncontrolled division and proliferation of lymphocyte populations—B-cells, T-cells, and natural killer (NK) cells—at different stages of their maturation and differentiation lead to a complex group of malignancies collectively known as lymphoma. These malignancies account for approximately 5% of all tumours worldwide and are marked by a striking diversity in their origin and development, clinical indications, biological behaviour, and therapeutic responsiveness. The complexity of lymphomas extends far beyond their cellular classification — with each subtype governed by distinct molecular and immunological patterns — leading to variable clinical outcomes. While the overall survival rate for lymphoma patients has significantly improved in recent years — with estimates now reaching 72% — survival outcomes remain highly contingent upon specific histological subtypes, genetic mutations, molecular aberrations, and the stage at diagnosis.

Lymphomas are broadly classified into two principal types: Non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL). This classification is based on both clinical presentation and the population of lymphoid lineage cells that proliferate abnormally and undergo malignant transformation. Non-Hodgkin’s lymphoma (NHL), the more prevalent of the two, is further divided into over 60 categories based on the specific subset of lymphocytes involved. B-cell NHL and T-cell NHL represent the major divisions, each encompassing numerous subtypes including Diffuse large B-cell lymphoma (DLBCL), Mantle cell lymphoma (MCL), Follicular lymphoma (FL), Marginal zone lymphoma (MZL), Primary mediastinal B-cell lymphoma (PMBCL), Burkitt’s lymphoma (BL), Post-transplant lymphoproliferative disorder (PTLD). HL tends to affect younger populations and generally has a more favourable prognosis compared to many forms of NHL, largely due to its responsiveness to contemporary therapies.

Causes and Current Treatment

The probable cause of lymphoma involves a complex interplay of genetic predisposition, environmental factors, and immunological dysregulation. Several risk factors (occupational exposure to carcinogens, infectious agents, Immunodeficiency, drugs, autoimmune diseases, geographic location, etc.) interact with the genetic makeup of humans in a complex manner resulting in the development of lymphoma (lymphomagenesis). The treatment of lymphoma is thus highly individualised, depending on the specific subtype of lymphoma, the stage of disease, patient factors, and underlying molecular and genetic characteristics. Conventional treatments for lymphoma—namely chemotherapy, radiation therapy, and stem cell transplantation—have long served as the foundational pillars of therapeutic intervention for this complex group of hematologic malignancies. These approaches, which have been subject to refinement over decades, remain indispensable in clinical practice and have significantly contributed to the improved prognosis and overall survival rates for many lymphoma subtypes.

However, despite their efficacy, these treatment modalities act as a double-edged sword and pose substantial challenges, particularly due to their nonspecific mechanisms of action, which do not discriminate between malignant and healthy cells. Conventional chemotherapy and radiotherapy may lead to severe adverse events in low‐risk lymphoma patients presumably because of their high potency but low tumour selectivity, while hematopoietic stem‐cell transplantation leads to disease recurrence in aggressive high‐risk lymphoma patients. All these factors necessitate finding innovative, novel approaches that explore sophisticated and precise treatment modalities.

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Research for new treatments

The complexity of lymphomagenesis remains an area of intense research, with a growing understanding of the intricate relationship between the immune system, environmental factors, and genetic mutations that drive this transformation. The classification of lymphomas into distinct subtypes based on lymphocyte origin, molecular characteristics, and clinical behaviour has paved the way for increasingly refined and personalised therapeutic strategies —marking a significant departure from the era of "one-size-fits-all" treatments. These studies have deepened our knowledge of lymphoma pathophysiology and opened new avenues for its treatment and prevention, particularly for individuals who are at elevated risk due to immunosuppressive therapies, chronic infections or autoimmune diseases. In the past, treatment options for relapsed or refractory lymphoma were limited, with many patients facing dismal prognoses after failing initial lines of therapy. However, clinical implementation of novel therapeutic modalities in immunotherapy, targeted therapy, and cellular therapies has revolutionised the field of oncology, yielding remarkable improvements in outcomes for lymphoma patients, particularly those with advanced-stage disease.

Promising Advancements

Immunotherapy marks a significant shift in lymphoma treatment and management by harnessing the body’s immune system to more effectively target cancer cells. Monoclonal antibodies (MAbs) and checkpoint inhibitors have been central to this transformation. mAbs, such as those targeting CD20 on B-cells, have dramatically improved survival in B-cell lymphomas like Diffuse large B-cell lymphoma (DLBCL) and Follicular lymphoma. Similarly, mAbs against CD30 are vital for managing relapsed or refractory Hodgkin’s lymphoma. When combined with chemotherapy, these therapies enhance response rates and prolong overall survival. By blocking proteins like PD-1 (Programmed Cell Death Protein 1) and PD-L1, checkpoint inhibitors restore the immune system's ability to detect and eliminate lymphoma cells, showing remarkable success in refractory or relapsed Hodgkin’s lymphoma.

In parallel, CAR T-cell therapy has redefined treatment for relapsed or refractory lymphomas. By genetically engineering a patient’s T-cells to express receptors that target specific antigens — such as CD19 on B-cell lymphomas — CAR T-cells exhibit precise and potent cytotoxicity against malignant cells. Clinical successes with therapies like axicabtagene ciloleucel and tisagenlecleucel have led to durable remissions, particularly in aggressive lymphomas like DLBCL and mantle cell lymphoma, positioning CAR T-cell therapy as a potentially curative option. Additionally, targeted therapies, such as Bruton’s tyrosine kinase (BTK) inhibitors like ibrutinib, have further advanced lymphoma treatment by inhibiting critical signalling pathways essential for the survival of B-cell lymphomas. These therapeutic options offer a more precise, effective and less toxic alternative to traditional treatments.

Challenges

While ex vivo genetically modified cellular immunotherapies have demonstrated remarkable clinical efficacy and commercial success, particularly in treating relapsed and refractory blood cancers, their development and large-scale manufacturing present significant challenges. These therapies are yet to reach their full potential due to the complexities involved in aligning cell biology with manufacturing processes. The manufacturing process for these therapies must navigate the intricate balance between optimising cellular growth and functionality while maintaining affordability and accessibility. This challenge involves a sophisticated understanding of cellular biology and process engineering. Key factors include enhancing process understanding and optimisation to improve product quality and yield. Despite their clinical promise, achieving cost-effective, reproducible, and robust manufacturing remains a major translational hurdle, with significant variability in the production process. Cell yield is a critical metric; for autologous therapies, higher yields shorten manufacturing times, while for allogeneic therapies, they enable more doses per batch, reducing costs.

DDE’s Contribution

DDE recognises that overcoming manufacturing challenges and realising the full potential of innovative cell and gene therapies necessitates a combined focus on optimising both yield and process robustness. To address these challenges, DDE is committed to scaling up biotechnological processes and advancing the use of automated closed systems. These systems are essential for improving manufacturing quality and efficiency, as they significantly reduce the risk of contamination and ensure the integrity of the final product. The integration of automation into bioprocessing enhances operational efficiency and reduces costs associated with large-scale production. By refining process control in the production of cell and gene therapy products, DDE aims to mitigate variability and ensure consistent product safety and efficacy. This approach is vital for improving the reproducibility of these therapies, facilitating their broader application, and enhancing their overall effectiveness.

DDE employs a Quality-by-Design (QbD) approach to systematically evaluate the impact of Critical Process Parameters (CPPs) on the Critical Quality Attributes (CQAs) of therapeutic cells during their expansion. This method ensures that every aspect of the biomanufacturing process contributes to high-quality product outcomes, aligning with rigorous regulatory standards and optimising therapeutic performance. Additionally, DDE’s modular, cGMP-compliant bioprocessing units enable optimal resource allocation and cost management, making high-quality bioprocessing accessible even in challenging locations. DDE solutions are designed to optimise energy consumption and minimise waste, contributing to more sustainable manufacturing processes and supporting the long-term viability of biotechnological manufacturing.?DDE is prepared to aid biopharma manufacturers in translating the remarkable clinical potential of immunotherapies into widespread, practical application — making these transformative treatments more accessible to a broader patient population.

FDA American Cancer Society Cancer Research UK (CRUK) Frederick National Laboratory for Cancer Research NCI Center for Cancer Research Cancer Research UK Science and Innovation Lymphoma Research Foundation The Leukemia & Lymphoma Society Lymphoma Action Lymphoma Canada Lymphoma, Leukemia & Myeloma Congress