Targeted therapies have shown significant promise in reducing relapse rates in high-risk non-Hodgkin’s lymphoma (NHL) by specifically attacking cancer cells while sparing normal tissues, thereby improving treatment efficacy and patient outcomes. These therapies include monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, small molecule inhibitors, and CAR-T cell therapies, all designed to exploit unique molecular features of lymphoma cells.
Non-Hodgkin’s lymphoma is a diverse group of blood cancers originating from lymphocytes, with some subtypes classified as high-risk due to their aggressive nature and tendency to relapse after standard treatments. Traditional chemotherapy and radiation have been the mainstay of treatment but often fail to prevent relapse in these high-risk cases. Targeted therapies aim to overcome these limitations by focusing on specific antigens or pathways critical to lymphoma cell survival and proliferation.
One of the earliest and most successful targeted approaches involves monoclonal antibodies against CD20, a protein commonly expressed on B-cell lymphomas. Rituximab, an anti-CD20 antibody, revolutionized NHL treatment by improving remission rates and survival when combined with chemotherapy. Building on this, radioimmunotherapy combines anti-CD20 antibodies with radioactive isotopes, delivering targeted radiation directly to lymphoma cells. This method has enhanced response rates and prolonged remission durations, especially when used in high doses alongside autologous stem cell transplantation, which helps patients recover from intensive treatment. However, despite these advances, relapse remains a challenge, partly because the radiation dose absorbed by tumors is limited by toxicity to normal tissues. Improving the targeting precision to increase tumor radiation dose without harming healthy organs could further reduce relapse risk.
Beyond CD20 targeting, newer bispecific antibodies such as epcoritamab, glofitamab, and mosunetuzumab engage the patient’s own T cells to recognize and kill lymphoma cells. These therapies have shown encouraging results in patients with relapsed or refractory NHL, including those who have exhausted other treatment options. By redirecting immune cells to attack lymphoma, bispecific antibodies can induce durable remissions and potentially lower relapse rates.
Small molecule inhibitors targeting signaling pathways critical for lymphoma cell survival, such as Bruton’s tyrosine kinase (BTK) inhibitors, have also emerged as effective treatments, particularly for rare lymphoma subtypes like mantle cell lymphoma and chronic lymphocytic leukemia. These oral agents disrupt intracellular signals that promote cancer cell growth and survival, offering an alternative for patients who do not respond to antibody-based therapies.
CAR-T cell therapy represents a groundbreaking approach where a patient’s T cells are genetically engineered to express chimeric antigen receptors that specifically recognize lymphoma antigens, most commonly CD19. This personalized immunotherapy has achieved remarkable remission rates in high-risk and relapsed NHL patients. However, some patients still experience relapse after CAR-T therapy, often due to residual disease or immune escape mechanisms. Recent research suggests that consolidative radiotherapy targeting residual lymphoma detected after CAR-T treatment can alter relapse patterns and improve local control and progression-free survival, indicating that combining targeted therapies with other modalities may further reduce relapse.
Clinical trials continue to explore combinations of targeted agents, such as pairing bispecific antibodies with novel immunomodulatory drugs, to enhance efficacy and overcome resistance. Early-phase studies are also investigating new molecules like ATG-031, aiming to expand the arsenal against refractory NHL.
In summary, targeted therapies have transformed the treatment landscape for high-risk non-Hodgkin’s lymphoma by providing more precise, effective, and less toxic options. While challenges remain, especially in preventing relapse, ongoing advances in antibody engineering, cellular therapies, and combination strategies hold great potential to improve long-term outcomes for patients facing this aggressive disease.
