Q&A with Paige Mahaney, Ph.D., Senior Vice President, and Corporate Head of Drug Discovery Research at Exelixis, Scientific.
BIOGRAPHY
Paige Mahaney has ~30 years of drug discovery leadership building clinical therapeutic portfolios in both small molecule and antibody therapeutics. She is an Advisory Board Member at Eurofins Discovery, key opinion leader in immnotherapeutcs discovery and development, and has served as committee chair for the American Chemical Society’s Division of Organic Chemistry and as a board member of BIO (Biotechnology Innovation Organization).
“A number of modalities beyond monoclonal antibodies have emerged as exciting opportunities to advance the immunotherapy landscape…”
-Paige Mahaney, Ph.D., Exilixis
Q&A
QUESTION: What pivotal advancements & transformative discoveries have you seen shape the field of immunotherapeutic (or cancer immunotherapeutic) drug discovery & development over the past two decades?
ANSWER: Cancer immunotherapy relies on the innate power of the immune system to recognize and kill cancer cells. However, the impact of immunotherapy extends well beyond the treatment of cancer to important advancements in the treatment of autoimmune disorders, allergies, and infectious diseases, among others. Arguably, the field of immunotherapy has entered its Golden Age in the past 20 years, due to revolutionary breakthroughs including immune checkpoint inhibitors, CAR-T therapy, immune-modulating antibodies, and cancer vaccines. In addition, the advancement of precision-medicine and technology enhancements in antibody generation and protein engineering has enabled the success of these new therapeutics.
Although the search for immune-based cancer therapies began as early as 1893 when durable and complete remission in several types of malignancies was achieved by injecting attenuated bacteria directly into tumors, the modern age of cancer immunotherapy began with the discovery of immune checkpoints by James Allison and Tasuko Honjo in the early 1990s. The discovery that these proteins [checkpoints] were preventing the immune system from attacking cancer cells led to the most transformational advancement in the field of cancer immunotherapy — the FDA/EMA approvals of the first immune-checkpoint inhibitors, Yervoy® (ipilimumab), Keytruda® (pembrolizumab), and Opdivo® (nivolumab) in 2011 and 2014. Along with newer anti-PD-1, and anti-PD-L1 monoclonal antibodies, these drugs have revolutionized the treatment of cancer by delivering effective immune-based therapies to broad cancer populations. To date, these therapies have been approved for more than 20 cancer types including, for some, as first-line monotherapies (Cancer Research Institute™ (CRI), 2024).
The successful discovery and clinical development of immune-checkpoint inhibitors leveraged important advancements in antibody generation and engineering as well as precision-medicine approaches. A few, noteworthy advances in therapeutic monoclonal antibody engineering include humanization approaches, generation of transgenic mouse strains that express human variable domains, the advent of in vitro phage display technologies, Fc engineering, B-cell sorting, and receptor sequencing. Also, it’s important to note, the clinical development program for pembrolizumab leveraged a precision enrollment strategy based on the expression of biomarkers that indicated which patients were likely to respond to treatment (6). Genentech had previously pioneered this approach for the clinical development of Herceptin® (trastuzumab), which was approved in 1998 for breast cancer patients who overexpress the protein HER2. Inclusion of patients who expressed the HER2 biomarker using a companion diagnostic test was critical for the success (and safety) of the drug (7).
Since 2000, very important advancements in immunotherapy were made beyond the checkpoint inhibitors. CAR-T cell therapy, for which a patient’s tumor-specific T-cells are engineered with the chimeric antigen receptor (CAR) in order to recognize and kill cancer cells, was first dosed in patients in 2010. This led to the approval of CAR-T cell therapies like Kymriah® (tisagenlecleucel) and Yescarta® (axicabtagene ciloleucel) for certain leukemia and lymphoma types. Immune modulating antibodies fine tune the immune response, either by enhancing or by suppressing specific immune responses. A significant number of anti-inflammatory monoclonal antibodies, e.g. anti-TNF, anti-IL17, anti-IL23, anti-IL4R, have been approved to dampen excessive immune response in conditions like rheumatoid arthritis, psoriasis, inflammatory bowel disease, and asthma.
Finally, significant recent advancements in cancer vaccines have been made targeting tumor-specific antigens, neoantigens or dendritic cells. To date, four preventative vaccines for cancers due to HPV or HBV infections and two therapeutic cancer vaccines for early bladder cancer and prostate cancer have been approved by the FDA.
QUESTION: What are the key limitations or hurdles that limit the potential of immunotherapy (or cancer immunotherapy) for the treatment of life-altering and/or life-threatening diseases?
ANSWER: While immunotherapy has shown remarkable success in treating certain types of cancer, several limitations remain including resistance and relapse, identification of biomarkers, toxicity, and cost and accessibility. Although checkpoint inhibitors have been approved to treat more than 20 cancer types (Cancer Research Institute™ , 2024), certain cancers, especially those with very low tumor infiltrating lymphocytes (TILs) or tumors that have lost their MHC class I expression, have limited response to current immunotherapies (11). In addition, some patients develop resistance over time. Understanding the mechanisms of resistance could help to expand the impact of immunotherapy to more patients.
Biomarkers used to predict a patient’s response to treatment have been an invaluable tool in the successful clinical development of immunotherapy. For example, responsiveness to immune-checkpoint therapy has been predicted by the level of expression of immune-checkpoint genes or by level of mutational load or microsatellite instability. However, good outcomes in patients with none of these biomarkers have also been reported. In addition, long term therapeutic outcomes differ significantly from patient to patient. Some patients have a durable, long-term response that can last for years while other patients develop resistance. A few patients have even seen a hyper-progression of their cancer after treatment. New biomarkers to better predict short-term response and longer-term outcomes are needed.
Immune-related adverse events, both acute and longer term, can limit the use of certain immunotherapies and affect patients’ quality of life. These events can be caused by an over-stimulation of the immune response, leading to an attack of healthy tissues, or an over-suppression of the immune response, leading to infection or development of cancer. Balancing efficacy with safety remains a key consideration.
Finally, immunotherapeutic drugs are expensive, raising concerns about cost-effectiveness and accessibility for patients, healthcare systems, and insurers. Ensuring equitable access to these life-saving treatments continues to be a critical issue.
QUESTION: What are some of the emerging paradigms & transformative trends that are poised to revolutionize the Immunotherapy space in the next decade? Do they address any of the current limitations of immunotherapy?
ANSWER: Several emerging trends in immunotherapy have the potential to further transform the field.
Approaches that have the potential to address resistance/relapse are:
- Rational combination strategies, including combining immunotherapies with chemotherapy, DNA-Damage Response inhibitors and TKIs have shown promise. However, to fully eradicate tumors, as postulated by Moynihan, et al. in 2016, a combination of multiple immunotherapies including a tumor-antigen targeting antibody, an immune-checkpoint inhibitor, a TCR vaccine, and a T-cell stimulating cytokine is required.
- A better understanding of interactions within the Tumor Microenvironment (TME), e.g. cross-talk between tumors and stromal cells, fibroblasts, immune cells, extracellular matrix, etc.
- Novel immunomodulatory agents that target checkpoints beyond PD-1/PD-L1 and CTLA4
- Modulation of the gut microbiome through probiotics, fecal microbiota transplants, etc.
- Non-invasive liquid biopsies that have the potential to better monitor treatment response, detect early signs of resistance and guide real-time treatment selection.
Approaches that have the potential to improve safety (and efficacy):
- Nano-sized particles and carriers to improve the delivery of immunotherapeutic agents, enhance their targeting to tumor sites, and reduce off-target toxicities.
- Next generation antibody-conjugates delivering immunotherapeutic agents, including STING agonists, immune-stimulatory cytokines, etc. to specifically interact with cancer cells.
- Bi- and tri-specific antibodies engineered to simultaneously target multiple antigens or immune cell types to enhance the specificity and potency of immunotherapy treatments.
Approaches that have the potential to identify novel predictive biomarkers are:
- Machine Learning and Artificial Intelligence that can be applied to analyze complex patient data, predict response to therapy, and guide the selection of personalized treatments including combinations.
- Advances in genomics, proteomics, and other omics technologies to enable more precise identification of biomarkers.
QUESTION: After immune checkpoints, what emerging therapeutic target classes or targets within immunotherapy drug discovery may attract significant attention and investment due to their potential to address unmet medical needs?
ANSWER: Cancer immunotherapies can be divided into two categories: those that stimulate a direct immune response and those that reactivate host immunity. Immune-checkpoint inhibitors can reactivate host immunity by releasing a braking mechanism applied by the immune system to prevent tissue damage caused by an overly aggressive immune response. Other approaches to reactivate host immunity include the use of immune-stimulating cytokines such as IL-2, IFN-a, and IL-12, and the removal of immunosuppressive cells such as myeloid-derived suppressive cells or tumor-associated macrophages. Host immunity can only be re-activated, however, when an existing immune response has become ineffective. If the cancer has fully evaded detection by the immune system, therapies aimed at reactivating immunity, including immune-checkpoint inhibitors, cannot be effective. Consequently, the most promising treatments for cancer types resistant to immune-checkpoint inhibitors are those that aim to stimulate a de novo immune response. Promising approaches under investigation in clinical trials are cancer vaccines with neoantigens that target driver mutations, tumor-infiltrating lymphocyte (TIL) therapy, oncolytic viruses that cause immunogenic cell death, and monoclonal antibodies directed to tumor-specific antigens that enhance immune-mediated cytotoxicity due to an engineered Fc domain.
An explosion of bispecific T-cell engagers in clinical trials has recently occurred – more than 100 are being investigated and more are rapidly advancing toward the clinic. T-cell engagers are intentionally designed to facilitate a T-cell-mediated immune response by binding concomitantly to a T-cell (most commonly via CD3 binding) and a tumor cell (via binding to tumor specific antigens). Proximity activates T-cell effector functions and redirects cell killing to the cancer cell. Toxicity concerns due to cytokine-release syndrome and neurotoxicity have led to the investigation of immune-directed agents that engage T-cell alternatives such as NK-cells.
A promising small-molecule approach to stimulating an immune response is via STING agonism. Activation of the STING pathway promotes antigen presentation enabling tumor recognition and activates T-cells toward tumor cell killing. To date, although a significant number of STING agonists have been assessed in patients, the potential of this pathway has not been confirmed. Presumably, the poor physiochemical properties of the molecules have limited their clinical translation and application. To overcome these challenges, various delivery systems including nanoparticles, hydrogel, and antibody-drug conjugates are being investigated.
It is important to note that any successful approach to stimulate a de novo immune response in cancer is likely to be limited by the immune system applying its natural braking system, i.e., upregulation of immune checkpoint proteins. Consequently, the maximum potential of these therapies will likely only be achieved in combination with immune checkpoint inhibitors.
QUESTION: In context of therapeutic modalities, beyond monoclonal antibodies, what are some of the other emerging modalities in the immunotherapy space do you anticipate changing the therapeutic landscape in the foreseeable future?
ANSWER: A number of modalities beyond monoclonal antibodies have emerged as exciting opportunities to advance the immunotherapy landscape including 1) improvements to CAR-T cell therapy and alternative adoptive cell therapy approaches, 2) Tumor Infiltrating Lymphocytes (TILs), 3) mRNA vaccines and RNA interference (RNAi) therapies, 4) oncolytic viruses, 5) gene editing technologies such as CRISPR/Cas9, and 6) small molecule immunotherapies such as STING agonists or adenosine receptor antagonists.
QUESTION: How does the drug discovery space perceive the relative merits of mechanism of action (MOA)-reflective, cell-based assays versus biochemical methods such as ELISAs for potency evaluation for immunotherapeutic development & potency lot release? What factors influence the choice between these two approaches?
ANSWER: The decision between MOA-reflective cell-based assays and biochemical methods depends on the specific characteristics of the molecule, the type of biological target, and how the assay results will be used. Very often, a combination of both types of assays are used to provide a comprehensive understanding of drug potency and quality. An important consideration is that specific agencies may have guidelines to ensure accuracy, sensitivity, and reproducibility, especially for regulatory filings. When considering factors that differentiate the two approaches, biochemical assays often provide higher specificity and sensitivity, enable better quantification, are more reproducible, and have higher throughput with lower cost. Cell-based assays are often preferred to assess complex, dynamic interactions within the cellular context, especially when protein complexes or protein-membrane interactions influence target activity.
QUESTION: Could you comment on desirable attributes of cell-based assays that align with the specific requirements of your research or drug development program, potentially influencing your decision-making process towards a solution that seamlessly integrates with and enhances the efficiency of your projects?
ANSWER: In discovery and translational research, cell-based assays should be designed to answer specific questions. We use cell-based assays to quantify very specific interactions, such as in-cell binding to the target as well as highly phenotypic assessments, such as cell proliferation and viability. Considerations for each type of assay will vary; however, the most important attributes of a cell-based assay are:
- Disease relevance – how closely the assay reflects physiologically-relevant interactions with the target and the biology of the target in the context of the disease
- Translatability – results from a cell-based assay should, ideally, correlate with in vivo efficacy
- Throughput – the throughput of the assay depends on how it will be used in the screening cascade
- Specificity – the assay should specifically measure the intended target or pathway
- Reproducibility – the assay should have low variability and be reproducible
- Dynamic range – the assay should be robust across a broad range of concentrations to allow for testing of weak and highly potent compounds