One area of research that has evolved rapidly in recent years is the identification and advancement of therapies that can fight disease by leveraging and boosting the immune system, known as immunotherapies. The immune system is highly complex and involves multiple cell types that mount an orchestrated response against foreign pathogens. This system comprises two distinct arms that work together to fight foreign invaders: the innate immune system, which provides the first line of defence against foreign cells; and the adaptive immune system, which refines the response and produces memory cells that attack repeat invaders and mediate long-term immunity.
We need a multifaceted approach to create strong therapeutics that are robust against variant drift for treating moderate-to-high-risk patients”
While selectively activating T cells is one crucial approach to cancer treatment, improved understanding of how memory B cells relate to cancer prognosis suggests there is also broad potential to leverage the existing capabilities of memory B cells to fight cancer.1 This article will focus on the humoral, or B cell‑related, portion of the adaptive arm of the immune system and how memory B cells can be leveraged in oncology.The majority of discussions and research on immunotherapy is focused on T cells – and for good reason. T cells, the arm of the adaptive immune system that moderates cell-mediated immunity, have long been recognised for their ability to control tumour growth and contribute to tumour regression. The idea that T cells are the major player for immune-mediated responses to cancer has become a leading therapeutic hypothesis across oncology research, in line with their ability to recognise abnormal cells. This has had important ramifications in the biopharma industry, most importantly for the development of immune checkpoint inhibitor therapies, which have revolutionised cancer treatment.
The relevance of memory B cells
B cells play an important role in the adaptive arm of the immune system by producing antibodies in response to antigen exposure, or specific motifs expressed by foreign bodies. These antibodies play a key role in our immune system by activating various pathways that ultimately lead to the neutralisation of pathogens. Once B cells encounter a pathogen, they also undergo rapid clonal expansion, providing the immune system with multiple clones of the parent B cell that originally encountered the pathogen. Some of these clones initiate antibody-mediated immunity by becoming plasma blasts, short-lived antibody-producing cells that rapidly release antibodies identical to the receptor that originally recognised the antigen.
Other daughter cells undergo a process referred to as somatic hypermutation, which iteratively improves the ability of the cell to bind the antigen. This process generates more effective daughter cells and ultimately results in memory B cells that can produce higher quality antibodies with greater affinity for antigenic targets. These cells mount a more efficient, higher quality immune response should they encounter the same antigens again in the future and lie dormant in secondary lymphoid tissue found in the lymph nodes and spleen, ready to be called upon when needed.2,3,5
B cells: a new path in immuno-oncology treatment
The key to leveraging memory B cells for cancer treatment lies in how they react when they are in a chronic inflammatory state (such as cancer), where the immune system will typically give rise to Tertiary Lymphoid Structures (TLS). TLS can often be found adjacent, or even within, tumour tissue and serve as a place of intense immunogenesis. Within the TLS, tumour-reactive naïve B cells are exposed to tumour-associated antigens and mature into memory B cells via a similar process to that described above. The memory B cells found in these tissues that matured in response to tumour-associated antigens are equipped with high affinity tumour-specific antibodies, which research suggests allows the immune system to mount a stronger anti-tumour immune response.4
We need a multifaceted approach to create strong therapeutics that are robust against variant drift for treating moderate-to-high-risk patients”
Researchers have shown that the density of B cells and extent of immune organisation within the tumour can serve as important prognostic factors in certain cancers.6 Recent studies have revealed that the presence of TLS, with deep infiltration of B cells and accompanying T cells, signalled a good prognosis for patients with melanoma, soft tissue sarcoma, lung cancer and invasive ductal carcinoma.1,5,8,9 This suggests that B cells are playing a more crucial role than previously thought and that their presence is indicative of a more co-ordinated anti-cancer immune response in which antibodies almost certainly play a role.
Using hybridoma technology to explore the potential of B-cell immunotherapies
If a patient’s B-cell response has a direct impact on disease outcome, it follows that we should shift our perspective towards how B cells are ‘seeing’ the tumour. Moreover, tissues in which these educated B cells are present, such as the tumour microenvironment (TME) and the draining lymph node, likely act as rich reservoirs for identifying both antibodies to treat cancer and tumour-specific antigens to which next-generation therapies can be targeted. Our core philosophy at Immunome is that an improved understanding of the antigens to which patients with strong anti-cancer responses are reacting, guided by a growing knowledge of where memory B cells reside and how they function within tumours, will lead to breakthroughs that benefit much broader populations of patients dealing with this devastating disease.
Progress in memory B-cell antibody-based treatments will be guided by ongoing research to improve our understanding of these cells’ role in fighting cancer and other diseases”
Immunome’s proprietary technology is used to isolate memory B cells from patients to create a large library of stable hybridomas, long-lived cells formed by fusion of normal lymphocytes and tumour (myeloma) cells.11 The antibodies produced by the hybridomas are identical to those made by the memory B cells and allow us to understand how patients’ immune systems saw and reacted to their disease in situ. This insight could potentially elucidate both novel targets on the surface of tumour cells and uncover tumour cell processes that could be targeted for therapeutic intervention. This is exemplified by IL-38, an understudied member of the IL-1 cytokine family, that was the target of an antibody isolated from the memory B cell of a head and neck cancer patient. Recent data from Immunome and others demonstrate the importance of IL-38 in regulating anti-tumour immunity.7,12
This therapeutic concept can and should also be expanded for infectious disease, which is especially relevant as the COVID-19 pandemic continues to evolve and threatens to become an endemic disease, with variants of concern continuing to rise. We need a multifaceted approach to create strong therapeutics that are robust against variant drift for treating moderate‑to-high-risk patients. We recently applied our hybridoma technology to isolate memory B cells from convalescent plasma of over 30 COVID-19 patients who were able to clear the virus quickly. From these we developed isolated hybridoma libraries, which we interrogated to inform development of our multi-antibody cocktail to treat COVID-19.10 These findings demonstrate that an unbiased approach to examining memory B-cell response may have significant advantages not only in cancer treatment, but also in infectious disease. Therapeutics can be rapidly developed via patient-directed memory B-cell interrogation and could be critical to contain not only the current pandemic but future endemic outbreaks within specific communities. Specifically for the ongoing COVID-19 pandemic, examining disease through the lens of human memory B cells can identify antibodies that go beyond the broadly known classes of SARS-CoV-2 epitopes to develop novel, variant-resistant treatments.13
Future progress in memory B-cell antibody‑based treatments will be guided by ongoing research to improve our understanding of these cells’ role in fighting cancer and other diseases. As that understanding evolves, the mantra of medical research endures: it is a matter of perspective. By shifting our perspective to look at disease through the eyes of the patient’s own cells and specifically their memory B cells, we can potentially unlock vulnerabilities within cancer cells or pathogens. This will allow us to develop new treatments that can strengthen our collective immunity against our common enemies of cancer and infectious disease.
About the author
Dr Purnanand Sarma serves as the President and Chief Executive Officer of Immunome. He brings more than 25 years of experience in all aspects of pharmaceutical industry business across multiple R&D platforms and was most recently the President and CEO of Taris Biomedical, which he built over nine years into a leader in therapeutic urology, focused on diseases such as bladder cancer and overactive bladder. Purnanand earned his PhD in pharmaceutics from the University of Minnesota and BPharm from Andhra University, Visakhapatnam, India.
References
- Cabrita R, Lauss M, Sanna A, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020;577(7791):561–5.
- Akkaya M, Kwak K, Pierce SK. B cell memory: building two walls of protection against pathogens. Nat Rev Immunol [Internet]. 2020;20(4):229–38.
- Largeot A, Pagano G, Gonder S, et al. The B-side of cancer immunity: The underrated tune. Cells [Internet]. 2019;8(5):449.
- Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature [Internet]. 2020;577(7791):549–55.
- Kinker GS, Vitiello GAF, Ferreira WAS, et al. B cell orchestration of anti-tumor immune responses: A matter of cell localization and communication. Front Cell Dev Biol [Internet]. 2021;9:678127.
- Sharonov GV, Serebrovskaya EO, Yuzhakova DV, et al. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nature Reviews Immunology. 2020;20(5):294–307.
- Takada K, Okamoto T, Tominaga M, et al. Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression. PLoS One [Internet]. 2017;12(7):e0181598.
- Petitprez F, de Reyniès A, Keung EZ, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature [Internet]. 2020;577(7791):556–60.
- DeFalco J, Harbell M, Manning-Bog A, et al. Non-progressing cancer patients have persistent B cell responses expressing shared antibody paratopes that target public tumor antigens. Clin Immunol [Internet]. 2018;187:37–45.
- DiMuzio JM, Heimbach BC, Howanski RJ, et al. Unbiased interrogation of memory B cells from convalescent COVID-19 patients reveals a broad antiviral humoral response targeting SARS-CoV-2 antigens beyond the spike protein. Vaccine X [Internet]. 2021;8(100098):100098.
- Pedrioli A, Oxenius A. Single B cell technologies for monoclonal antibody discovery. Trends Immunol [Internet]. 2021;42(12):1143–58.
- de Graaf DM, Teufel LU, Joosten LAB, Dinarello CA. Interleukin-38 in health and disease. Cytokine. 2022;152:155824 .
- Nikitin PA, DiMuzio JM, Dowling JP, et al. Preclinical efficacy of IMM-BCP-01, a highly active patient-derived anti-SARS-cov-2 antibody cocktail [Internet]. bioRxiv. Cold Spring Harbor Laboratory
