Pursuing Precision Immunotherapy for Cancer: Approaches and Challenges

Technology Networks recently had the pleasure of speaking with Prof. Stephen Schoenberger of La Jolla Institute for Immunology to learn more about his laboratory’s work, directed towards achieving a comprehensive mechanistic understanding of the generation and regulation of T-cell responses in the context of infection and cancer development.

Schoenberger discusses the concept, promise and challenges of precision immunotherapies, and explains how synthetic biology approaches can be used to develop such therapeutics.

Q: What is the goal of precision immunotherapy, and how does this approach differ to other immunotherapeutic approaches?

A: Broadly speaking, immunotherapy involves the application of strategies through which various components of the immune system can be directed to eradicate cancer. To-date, this has involved both leveraging positive signals, such as cytokines that promote growth/effector functionality in specific cellular subsets or antibodies that engage costimulatory pathways, as well as methods of uncoupling inhibitory signalling pathways that otherwise restrain the anti-tumor immune response. Although each of these approaches has had a degree of success in specific settings, their effects are not universal across all cancer types, and often come with an appreciable risk of undesired immune damage to normal tissues. This is perhaps understandable when one unleashes the power of the immune system but does not control it’s targeting. Precision immunotherapy seeks to address this critical issue of tumor-specific targeting to ensure that the potency of the immune system is directed specifically at the cancer cells while minimizing collateral damage to normal cells. The surest way to achieve that – at present – is to target features that are specific to the tumor.

Q: How can synthetic biology be leveraged to aid the development of precision immunotherapies?

A: I believe that the greatest impact of synthetic biology will be in the development of more powerful and precise therapeutic vaccines. Cancer is a genetic disease, meaning it results from specific gene mutations, that alter cells’ normal functioning and can give rise to neoantigens. These antigens, encoded by tumor-specific mutated genes, are displayed exclusively on the surface of “transformed” cells. A key goal of precision immunotherapy is to identify the subset that can serve as “neoantigens” that are recognized by a patient’s T cells and then to activate/amplify this response. Synthetic biology, and specifically nanoengineering, offer entirely new possibilities for leveraging the potential of the immune system to mount a powerful and coordinated attack on the tumor that is both achievable on a patient-specific basis and scalable. The challenge now is to understand the components of a rationally-designed synthetic vaccine that can induce the desired therapeutic response from the natural biology of a cancer patient’s immune system.

Q: Can you please elaborate on your lab's work focused on exploring the mechanistic underpinnings of T-cell responses, both in response to infectious pathogens and during cancer development?

A: I’m fortunate to have received my training in immunology at a time when the fundamental rules that govern the response of T cells to both infectious pathogens and normal self were first being understood at the cellular and molecular level. Since my post-doctoral training with Prof. Kees Melief at the University of Leiden, I’ve sought to apply this emerging knowledge to explore whether the same mutations that define the transformed state in cancer cells could be targets for immune recognition and destruction by CD4⁺ and CD8⁺ T cells. To approach this, I first needed to understand how T cells work, and have pursued this goal in the context of experimental models of microbial infection, autoimmunity and cancer for over 20 years. During that time, my lab has made contributions to the understanding of CD4⁺/CD8⁺ T cell regulation and have identified some of the genes and pathways that govern this. In parallel, remarkable progress in the field of immunology has produced a body of knowledge that enables an integrated and holistic view of immunity and the parameters that influence the class, magnitude, specificity and regulation of immune responses. The emerging view is that tumors occupy a special niche within the context of immunity. They are clearly different than normal cells because of the mutated proteins they express, and should therefore be recognizable by the immune system, but lack the molecular features of infectious pathogens that are needed to initiate and amplify that response.

Q: Can you talk to us about the concept of a vaccine design for certain types of cancer, and how the work of your lab helps to inform research in this space?

A: The work in my lab towards vaccine design has proceeded along two main paths: targeting and delivery. Through the first path, we have pursued methods of identifying which mutations expressed in a tumor represent therapeutically-actionable targets; which mutations can serve as neoantigens, in other words. The advent of rapid and cost-effective genomic sequencing has made the routine identification of expressed mutations in cancer widely possible, and much effort in the field of immuno-oncology has been applied towards determining which of these can be "seen" by the patient’s immune system, with the overwhelming majority of these taking a predictive computational approach. We have taken a different tack on this, and one based on the assumption that within the cancer patient, the immune system has already mounted a physiological T-cell response to a subset of the expressed mutations that is quantitatively small and therapeutically ineffective, but which can be expanded and empowered through vaccination to eradicate disseminated metastases. The second arm of this effort is focused on methods to improve the specificity, potency and durability of therapeutic vaccine-induced T-cell responses based on an integrated holistic view of the immune system. These efforts involve coordination of the innate and adaptive arms of the immune system, synergies between CD4⁺ and CD8⁺ T cells, and evaluating vaccine formulations that are both potent and cost-effective, and which can be produced rapidly enough to meet clinical needs of the patient. There are a number of challenges, but I am convinced that these can be overcome to make the routine and reliable delivery of effective personalized cancer vaccines a clinical reality.

Q: What key challenges remain in pursuing precision immunotherapy?

A: Progress in the research space has raised the hypothetical foundations of precision immunotherapy to the level of proof – it is now clear that when properly targeted and delivered in sufficient numbers, T cells can eradicate disseminated metastatic cancer. The main challenges, to me, are to understand the mechanistic details underlying successful immunotherapy, to learn the reasons why it works and under what conditions, and then to devise ways in which this information can be applied widely in the setting of community-level oncology. This will require approaches that can quickly move academic discoveries to clinical evaluation and, if successful, to a manufacturing process that is rugged and scalable. This will take new thinking at every level to ensure that scarce resources are directed to not only that which is possible – but almost from inception to that which is feasible.

Q: How do you envision your research focus and the technologies that you adopt might evolve over the forthcoming years?

A: A central feature of science is that new and often unanticipated technologies can enable huge leaps forward in what’s possible, and I’ve witnessed this numerous times in my own field in the form of flow cytometry, peptide/MHC tetramers, transgenic mice, laser-confocal microscopy, next-generation sequencing and CRISPR-based genome engineering among others. Although we do not usually focus on their development, I’ve tried to stay aware of new technologies and incorporate them into our research when I can understand and appreciate their potential. At heart, however, I’m a relatively simple biologist who tends to focus on one question at a time, and at present, that is to understand whether cancer patients possess within their own immune system the capacity to recognize the mutations that define and distinguish cancer and eradicate it based on those differences.

Technologies that will aid in answering that question, and do so for the clinical benefit of cancer patients, will be those that allow insights into the mutations expressed by the cancer and the immune response, earlier, with greater sensitivity and in a less-invasive manner than what’s currently possible. A fundamental change in my approach to this scientific problem has been necessarily compelled with the switch from experimental clinical models to our current situation, in which every case we study is a fellow human who has a reasonable expectation to benefit from technological advances to make their treatment more precise, effective and tolerable. Towards that, I’m encouraged by advances in the imaging of cancer,  liquid biopsy technologies and single-cell sequencing that can allow unprecedented insights into the cancer genome and the T-cell response, and expect that progress in these areas will be crucial to our research goals.

Professor Stephen Schoenberger was speaking with Molly Campbell and Laura Elizabeth Lansdowne, Science Writers, Technology Networks.