New immune-based approaches stir hope in non-Hodgkin’s lymphoma

Non-Hodgkin’s lymphoma (NHL), one of the most common hematologic cancers in the U.S.,¹ is a heterogeneous group of diseases with more than 60 identified subtypes.² Each subtype is characterized by distinct clinical presentation, morphology, and underlying genetics. With distinct clinical and biologic profiles, each subtype requires a different approach.

Scientists at Genentech and across the scientific community are working diligently to better understand NHL with the goal of offering patients with diverse subtypes of NHL treatment solutions that are precisely right for them. Recent discoveries have laid the foundation for two novel treatment approaches for these complex, difficult-to-treat hematologic cancers – antibody-drug conjugates (ADCs) and T-cell bispecific antibody cancer immunotherapies.

More options are needed

All forms of NHL are driven by malignant transformation of lymphoid cells, primarily within the lymph nodes, but also in the bone marrow, spleen, and gastrointestinal tract.³ Historically, NHL has been treated with chemotherapy given as monotherapy or in combinations, and, in some cases, in combination with other treatment modalities such as immunotherapy or radiation.

FDA-approved treatment options for NHL are currently limited, and resistance to existing therapies or relapse following initial treatment is common and many times aggressive. Treatment approaches are sometimes limited depending on disease stage and patient characteristics such as age, frailty, and comorbidities.⁴

B-cell NHL arises from B-cells,⁵ but other subtypes may arise from T-cells or NK cells, known for their ability to directly kill virus-infected cells and cancer cells. The origins of the cancer help determine the subtype and treatment course.⁶ Although chemotherapy can be effective, its toxicity can be harmful to all cells, not just cancer cells.⁷ Chimeric antigen receptor (CAR) T-cell therapy, which uses a patient’s reengineering immune cells to attack cancer, can be effective, but logistical challenges may limit its wide use across a variety of treatment settings, including community-based care.⁸

Pioneering science

The introduction of antibody immunotherapy has changed the cancer treatment landscape, and its potential is only starting to be fully tapped. ADCs and bispecific antibodies have built on learnings from antibody science and offer hope to patients and physicians alike. These approaches may offer new treatment options in cancers like diffuse large B-cell lymphoma (DLBCL), the most common type of aggressive NHL. An estimated 40 percent of patients with this type of NHL relapse after initial treatment.⁹

ADCs are one advancement in immunotherapy that allows delivery of chemotherapy directly to cancer cells, mitigating some of the toxicity and side effects associated with systemic chemotherapy.¹⁰ An early innovator in ADCs, Genentech is credited with developing a technology that helped enable ADCs to directly target disease-causing cells. Genentech scientists engineered a novel linker that can be used interchangeably with different antibody-based medicine combinations. This adaptable system allows for mixing and matching of antibodies and linkers to develop the most stable and effective ADC medicine. Genentech has already received FDA approval for two ADCs.

A newer innovation in immunotherapy, T-cell engaging bispecific antibodies are designed to recruit the immune system to destroy cancer cells by engaging with two different targets simultaneously – for example, CD20 on the blood cancer cell and CD3 on the T-cell.¹¹ Because this treatment bypasses the need for cell collection and genetic engineering, it carries the potential for administration in the community setting at local facilities rather than just at large academic treatment centers, increasing accessibility for patients. It may better meet the needs of some people with hematologic cancer.

Although the idea for creating bispecifics had been around for nearly half a century before the first bispecifics were developed, the difficulty in actually building them impeded progress. With a typical antibody, both “halves” of the Y shape are identical. To successfully engineer a bispecific, each “half” isn’t identical – rather, each must be designed to engage separate molecular targets. Additionally, these pieces from two different antibodies must assemble in a particular way to be effective.

Genentech developed a technology called “knobs-into-holes” that solved the challenge of assembling in a particular way to engage separate molecular targets, enabling early bispecific antibody engineering and allowing for the innovation seen today in bispecific development.¹² Genentech is now working to bring bispecific medicines to people with NHL as early as next year.

Bispecifics and ADCs are two key approaches that have the potential to help improve the treatment experience, and ultimately outcomes, for patients, including the estimated 80,000 people in the U.S. expected to be diagnosed with NHL in 2021.¹³ New treatments create opportunity to revolutionize the way the medical community treats hematologic cancers.

To learn more, visit Genentech’s Hematology Hub.

¹ Key Statistics for Non-Hodgkin Lymphoma. American Cancer Society. 2021.Accessed from: https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/key-statistics.html
² NHL Subtypes. Leukemia and Lymphoma Society. 2016. Accessed from: https://www.lls.org/lymphoma/non-hodgkin-lymphoma/nhl-subtypes
³ Types of B-cell Lymphoma, American Cancer Society. 2019. Access from: https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/b-cell-lymphoma.html
⁴ Treating Non-Hodgkin Lymphoma. American Cancer Society. 2021. Accessed from: https://www.cancer.org/cancer/non-hodgkin-lymphoma/treating.html
⁵ Types of B-cell Lymphoma. American Cancer Society. 2019. Accessed from: https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/b-cell-lymphoma.html
⁶ Types of T-cell Lymphoma. American Cancer Society. 2018. Accessed from: https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/t-cell-lymphoma.html
⁷ Chemotherapy for Non-Hodgkin Lymphoma. American Cancer Society. 2018. Accessed from: https://www.cancer.org/cancer/non-hodgkin-lymphoma/treating/chemotherapy.html
⁸ CAR T-cell Therapy and Its Side Effects. American Cancer Society. 2021. Accessed from: https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/car-t-cell1.html
⁹ Maurer JM, et al. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol. 2014;32:1066-73.
¹⁰ Hitting the spot. Genentech. 2019. Accessed from: https://www.gene.com/stories/hitting-the-spot?topic=oncology
¹¹ About Bispecific Antibodies. Genentech. 2021. Accessed from: https://www.genentechoncology.com/development-platforms/bispecific-antibodies.html
¹² A Bispecific Revolution. Genentech. 2017. Accessed from: https://www.gene.com/stories/a-bispecific-revolution
¹³  Key Statistics for Non-Hodgkin Lymphoma. American Cancer Society. 2021.Accessed from: https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/key-statistics.html