Non-Hodgkin's Lymphoma (NHL), a heterogeneous group of lymphoid malignancies, has seen a paradigm shift in its treatment approach, driven by the evolution of immuno-oncology.

This subset of cancer immunotherapy harnesses the patient's own immune system to identify and eradicate malignant lymphocytes, offering precision and durability unmatched by conventional cytotoxic regimens.

As of 2025, immuno-oncology agents are no longer reserved for relapsed cases—they are becoming front-line contenders, particularly in aggressive subtypes such as Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL). According to Dr. John Timmerman, a lymphoma expert at UCLA's Jonsson Comprehensive Cancer Center, "Immunotherapies are altering survival trajectories in ways we hadn't imagined five years ago—what was experimental is now foundational."

Checkpoint Inhibitors in NHL: Limited but Strategic Roles

Unlike solid tumors, where PD-1/PD-L1 blockade has revolutionized care, the benefit of checkpoint inhibitors in NHL is subtype-dependent. Agents such as nivolumab and pembrolizumab have demonstrated efficacy in primary mediastinal B-cell lymphoma (PMBCL) and relapsed classical Hodgkin's lymphoma, but show variable outcomes in common NHL subtypes.

Recent Phase II data published in The Lancet Haematology (2024) demonstrated that pembrolizumab plus bendamustine and rituximab achieved an overall response rate (ORR) of 48% in relapsed FL, although durable responses were confined to a molecularly defined subset with high tumor mutational burden and PD-L1 expression.

This underscores the importance of biomarker stratification, as not all NHL subtypes exhibit the immunogenic features that predict checkpoint sensitivity. Trials are ongoing to enhance response by combining checkpoint blockade with immunomodulatory drugs (IMiDs), monoclonal antibodies, or epigenetic modifiers.

CD19-Directed CAR-T Cell Therapy: Expanding Indications and Efficacy

Among the most transformative advances in immuno-oncology for NHL is Chimeric Antigen Receptor T-cell (CAR-T) therapy, particularly targeting CD19, a B-cell surface antigen expressed in most B-cell lymphomas. The FDA approvals of axi-cel (Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (Breyanzi) have provided therapeutic lifelines to patients with relapsed/refractory DLBCL and other aggressive NHLs.

A 2023 long-term follow-up of the ZUMA-7 trial, published in NEJM, reported a 2-year event-free survival rate of 41% with axi-cel used as second-line therapy in DLBCL, compared to 16% with standard salvage chemotherapy and autologous stem cell transplant (ASCT).

Moreover, recent innovations such as dual-targeted CARs (e.g., CD19/CD22 or CD19/CD20) are in development to counter antigen escape—a major cause of post-CAR relapse. Trials like TRANSCEND FL are evaluating the role of CAR-T in indolent NHL, expanding its application beyond high-grade disease.

Bispecific Antibodies: Off-the-Shelf Immunotherapy in Practice

Bispecific T-cell engagers (BiTEs) represent a major breakthrough by linking T cells to lymphoma cells without the need for personalized cell manufacturing. Mosunetuzumab, a CD20xCD3 bispecific antibody, gained FDA approval in late 2023 for relapsed/refractory FL after at least two prior lines of therapy.

Phase II results presented at the 2024 ASH Annual Meeting showed a complete response rate of 60% with mosunetuzumab monotherapy, along with a manageable safety profile—primarily low-grade cytokine release syndrome (CRS) and minimal neurotoxicity. Other agents like glofitamab, epcoritamab, and odronextamab are under active investigation across various NHL subtypes. These agents are especially promising for outpatient administration and rapid disease control in frail or elderly patients.

Modulating the Tumor Microenvironment (TME): The Next Frontier

The immunosuppressive milieu within the TME remains a formidable barrier to effective therapy in many NHL variants. Research is now focused on reprogramming the TME by targeting myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and checkpoint ligands expressed by stromal cells.

Agents such as magrolimab (anti-CD47), which enhances macrophage-mediated phagocytosis, and tenalisib, a PI3K-δ/γ inhibitor with TME-modulatory effects, are currently in early-phase trials. These approaches are anticipated to synergize with existing immunotherapies and reduce immune evasion mechanisms.

Safety, Toxicity, and Real-World Integration

Despite promising efficacy, immunotherapies carry substantial risks. CAR-T-related toxicities, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), require specialized inpatient care. Efforts are underway to develop predictive algorithms using machine learning and cytokine kinetics to identify patients at high risk of severe complications.

Bispecific antibodies, although less toxic, may still induce CRS. However, step-up dosing regimens and prophylactic corticosteroids have significantly mitigated this issue in clinical practice. Dr. Loretta Nastoupil from MD Anderson notes, "We are improving not only on the science of immunotherapy, but on its operational delivery—ensuring safe administration outside academic centers."

Future Outlook and Clinical Implications

Looking ahead, the integration of multiomic profiling, liquid biopsy, and adaptive trial design will refine patient selection and response monitoring in immuno-oncology for NHL. Additionally, next-generation CAR-Ts incorporating memory T cell subsets, or armored constructs (such as IL-12-secreting CARs) are progressing through early clinical trials.

Global registries, such as the CIBMTR CAR-T Outcomes Database, are facilitating longitudinal assessment of real-world effectiveness and durability. The hope is to eventually position immunotherapy not only as a salvage option but as a curative modality in first-line treatment strategies.

Immuno-oncology has revolutionized the therapeutic algorithm for Non-Hodgkin's Lymphoma, with therapies that engage the immune system more precisely than ever before. As we step into 2025, clinicians must remain adept at navigating a complex therapeutic landscape—balancing efficacy, toxicity, cost, and logistics. The future of NHL treatment lies in rational immunotherapy combinations, robust biomarker use, and tailored patient selection—all aimed at translating scientific promise into durable patient outcomes.