Decoding the Immune System

Our immune system is the vital gatekeeper between us and disease, fighting off invading pathogens and maintaining a careful balance between responsiveness and overreaction. When it goes wrong however, the consequences can be devastating. A lack of response can leave us open to infections, as seen in HIV patients and those undergoing immunosuppressive therapies. An over-reaction to something harmless or to our own tissues leads to allergy and autoimmunity. An absence of recognition of aberrant cells in our own body can see progression to cancers. This brings into sharp focus just how important and how finely tuned this system must be to maintain good health.

The interplay between the many facets of our immune system with one another and the rest of our body’s cells and systems is incredibly complex, involving many cell types and chemical signals all working in harmony. With such a complex system, developing a complete understanding is an enormous undertaking but one to which scientists have been striving.

We spoke Dr Daniel Pregibon, SVP, Head of Platform Discovery and Technology at Repertoire, about the importance of decoding the immune system, how they are working towards this goal and ways in which their work can contribute to fighting the current pandemic.

Karen Steward (KS): Can you tell us a bit about how Repertoire came to be founded? What are the main aims of the company?

Daniel Pregibon (DP): Repertoire Immune Medicines, a Flagship Pioneering company, is a clinical-stage biotechnology company working to unleash the remarkable power of the human immune system to prevent, treat or cure cancer, autoimmune conditions and infectious diseases. The company was formed from the merger of Cogen Immune Medicines, a preclinical immune discovery company, and Torque Therapeutics, a clinical stage immune-oncology company, forming a fully integrated immune discovery and therapeutics company. Repertoire is comprised of approximately 120 individuals, which include 60 persons from each legacy company, and is headed by CEO John Cox (formerly of Bioverativ and Biogen). The company is dually located in Cambridge, MA and has an additional fully owned subsidiary named Tepthera Therapeutics in Zurich, Switzerland.

Repertoire has built a suite of technologies that elucidate T cell reactivity to disease-associated antigens in order to deploy and monitor potent T-cell mediated immunotherapies. These technologies further support the company’s product development engine that is composed of advanced nanoparticle-based immune modulators and antibody-tethered cytokines that sustain and amplify the activity of its T cell products, modular and minimal-footprint cellular manufacturing capabilities, and a full clinical and translational in-house support team. Repertoire’s initial product offering is nanoparticle-IL15-supported multi-antigen-targeted autologous T cells that are currently in Phase I clinical trials against multiple malignancies. The company is further utilizing its advanced discovery capabilities for deployment of additional cellular and acellular therapeutics for multiple indications, which include autoimmune and infectious diseases.

KS: The immune system is incredibly complex, where do you begin with decoding it?

DP: At Repertoire Immune Medicines, we believe that decoding the universe of T-cell receptor (TCR) - antigen codes that drive health and disease will be one of the greatest advancements in medical science. We have developed a suite of DECODE™ technologies that allow in-depth characterization of the immune synapse with unprecedented precision. The company leverages cellular and acellular platforms to thoroughly understand the presentation of antigens in disease, de-orphan both CD4+ and CD8+ TCRs in the context of single-cells, and curate vast amounts of data to enable deep-learning computational prediction models.

KS: Why is it important to decode the immune system?

DP: The human immune system is arguably the most complex and elegant creation of biology. It is a proactive, individualized immune security system generated by a nearly infinite recombination of specialized receptor genes, protecting us on a daily basis from pathogens and abnormalities. Conversely, the aberrant function of the immune system leads to heightened risks for infections from environmental pathogens, increased rates of tumorigenesis, and initiates autoimmune dysfunction that compromises the performance of our vital organs.

Decoding the immune system will provide a fundamental understanding of how we can design, maintain or restore immune repertoires to promote survival by protecting us from infection, cancer, and even old age. By decoding the immune system, we hope to uncover novel biomarkers that fundamentally redefine healthy and diseased states, that support the development of more efficacious therapies that harness the body’s own restorative powers, and that will help to ameliorate maladaptive responses that compromise our longevity.

KS: Can you tell us about some of the techniques that are key in decoding the immune system? Would these types of studies have been possible five or ten years ago?

DP: Repertoire has three platforms that work in unison to systemically decode the immune system – CIPHER, MCR, and CAPTAN. The company’s CIPHER platform leverages large libraries of proprietary barcoded peptide-major histocompatibility complex (pMHC) multimers to stain primary T cells for interrogation by single cell RNA sequencing (scRNA-seq), affording a sensitive read out of the immune code (TCR-pMHC and phenotype) on a cell by cell basis. The MCR platform is a mammalian cell line reporter system that enables unbiased interrogation of candidate TCRs against a nearly unlimited set of pMHC, thereby deorphaning the TCR specificities of disease-relevant clonotypes. Finally, the CAPTAN platform is the Company’s computational engine that will be elaborated upon shortly, vide infra. Each of these platforms constitutes the state of the art in high-throughput interrogation of CD8+ and CD4+ T cell repertoires across a broad range of diseased states. Afforded by a rapid advancement in technology, such interrogations would not have been possible at this level of diversity and automation even two years ago.

KS: You mention AI, where does that fit into the picture?

DP: The company’s CAPTAN platform is a computational engine that utilizes proprietary algorithms and artificial intelligence to provide analytical insights from our experimental data and develop machine learning models to eventually predict synapse codes well beyond our experimental capabilities. CAPTAN is intimately interlinked with our CIPHER and MCR platforms, which provide training and validation data for continuous improvement, and taken together – these systems provide the most in-depth decoding of the immune system conducted to date.

KS: How can the information you discover about the immune system be translated into tackling disease? In the context of the current COVID-19 pandemic, how can this information be utilized to help reduce the spread and treat disease?

DP: Long-term protection against SARS-CoV-2, or other threats, requires the development of T cell memory. When a virus like SARS-CoV-2, flu, the common cold, or HIV infects our tissues, our cells will break down the virus proteins and present them as peptide fragments on the cell surface, where they can be recognized as antigenic by specific T cell clones in our repertoires. Upon engagement, these clones then proliferate to produce millions of T cells with identical reactivity. This army of T cells is mobilized, destroying cells anywhere in the body presenting those same antigenic peptides. This constant surveillance by our T cell repertoires help orchestrate a productive, long-term immune response.

The dynamics of SARS-CoV-2 infection is yet to be fully understood, and it is unknown whether patients acquire long-term immunity to the virus following initial infection. The majority of current investigations into COVID-19 vaccines focus on the B cell derived antibody responses to a handful of viral targets, typically those derived from the spike, membrane and nucleocapsid proteins. Repertoire’s immune decoding capabilities have the potential to identify antigen molecules that induce a robust T cell response for inclusion in vaccines, and reveal the key to long-term immunity resulting from responses to any protein of SARS-CoV-2, or other cross-reactive coronaviruses, which will significantly expand the scope of vaccine development.

Dr Daniel Pregibon was speaking to Dr Karen Steward, Science Writer for Technology Networks.