Precision medicine promises a new paradigm in oncology where every patient receives truly personalized treatment. This approach to disease diagnosis, treatment and prevention utilizes a holistic view of the patient—from their genes and their environment to their lifestyle—to make more accurate decisions.

Growing at a rate of 10.7 percent, the precision medicine market is expected to exceed $96 billion by 2024.¹ Bioinformatics represent a significant share of the market, as bioinformatics tools enable the data mining necessary for rapid identification of new drug targets and repurposing of existing treatments for new indications.¹ (Reuters) The oncology segment of the precision market is expected to experience an 11.1 percent compounded annual growth rate (CAGR) leading up to 2024 due to the success of recent targeted therapies and subsequent high demand.

Still, precision medicine is in its infancy, and making personalized treatment a reality for all patients requires a transformation in how novel therapies are developed and delivered. New regulatory, technical, clinical and economic frameworks are needed to ensure that the right patients are able to access the right therapy at the right time. In this article, we review the current state of precision medicine in oncology and explore some of the challenges that must be addressed for precision medicine to reach its full potential.

Precision medicine and cancer immunotherapy
Great strides toward precision medicine are being made in the area of cancer immunotherapy, which is designed to boost a patient’s own immunity to combat tumor cells. The introduction of immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 inhibitors) revolutionized treatment for certain hematologic malignancies and solid tumors. To date, immune checkpoint inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for more than 15 cancer indications, but their widespread use has been hampered by unpredictable response rates and immune-related adverse events.

The approvals of the first chimeric antigen receptor (CAR)-T cell (CAR-T) therapies in 2017 were the next leap forward in precision medicine. These immunotherapies demonstrated that it was possible to take out a patient’s own T-cells, genetically modify them, and then put them back in to target cancer cells. With complete remission rates as high as 83 percent within three months of treatment, CAR-T therapies represent a seismic shift in our approach to cancer, bringing the elusive possibility of a cure one step closer. However, longer-term follow-up has shown that these remissions may not be durable² and prevention of relapse must still be studied.

Approaches to cancer immunotherapy
Ultimately, the goal of cancer immunotherapy is to stimulate the suppressed immune system of a patient with cancer so that it can launch a sustained attack against tumor cells.³ This is complicated, as the interactions between tumors and immune system—sometimes called the Cancer-Immunity Cycle (see Figure 1 in the slider above)⁴—are complex and dynamic. The Cancer-Immunity Cycle manages the delicate balance between the immune system’s ability to recognize non-self and the development of autoimmunity.

In some cases, the immune system may fail to recognize tumor cells as non-self and may develop a tolerance to them. Moreover, tumors have an armamentarium of methods for evading the immune system. Given this elaborate interplay between cancer and immunity, there is a wide range of potential cancer immunotherapy approaches:

• Monoclonal antibodies. Synthetic versions of large proteins with a unique antigen specificity that allows them to bind to cancer cells or target the tumor microenvironment. Immune checkpoint inhibitors fall into this category.
• Cancer vaccines. Use of a vaccine to encourage the body to develop anti-tumor antibodies.  These vaccines may contain whole cancer cells, parts of cancer cells, or purified antigens that enhance the immune response against the cancer.
• Cell-based immunotherapy. Unlike the approaches above which are designed to stimulate an immune response, cell-based immunotherapies contain intrinsic anti-tumor properties.⁵ Adoptive T-cell transfer, such as chimeric antigen receptor (CAR)-T therapy, and therapeutic tumor-infiltrating lymphocytes fall into this category.

Overcoming mechanisms of resistance
Resistance to immunotherapy may be primary (failure to respond) or secondary (relapse after successful treatment. Approaches for optimizing response and minimizing resistance to cancer immunotherapies include developing biomarkers to assist with patient selection or monitor response, altering the tumor microenvironment, and educating healthcare practitioners on the potential for delayed response with these types of treatments. With CAR-T therapies, resistance may be due to poor persistence of CAR-T cells following infusion or due to antigen loss, whereby cancer cells develop resistance by losing the receptor targeted by the CAR-T cells.

Moving toward combination therapies
The immune response to cancer involves a series of carefully regulated events that are optimally addressed as a group, rather than individually.⁴ The complexity of the immune response to cancer provides a strong rationale for combination therapies, for instance:

• Immunotherapy/Immunotherapy. Two immunotherapies targeting different immune checkpoints.
• Immunotherapy/Chemotherapy. Direct killing of tumor cells with chemotherapy may help activate the immune system and lead to an additive effect for immunotherapy.
• Immunotherapy/Targeted therapy. For example, anti-VEGF therapy may stimulate the immune system and inhibit tumor vascularization, creating a possible synergistic effect with immunotherapy.

Rethinking the drug development process
Pharmaceutical business models have traditionally focused on broad drug development and blockbuster drugs. Widespread success of precision medicine will require a fundamental change in the way the industry operates, as regulatory agencies typically require large phase III trials to support marketing approval. The nature of precision medicine requires smaller clinical trials in targeted patient populations, and the entire development process will need to be rethought to make these trials—and their resultant therapies—safe and economically viable for both sponsors and patients.

Harnessing genomic data
Increasingly, the development and deployment of immunotherapy relies on harnessing genomic data to identify the patients most likely to respond to immunotherapy and to customize immunotherapy for a given patient.⁶ Thus, molecular profiling technologies, such as next-generation sequencing, have become integral to drug development and patient selection. At the same time, researchers are focusing on identifying molecular alterations in tumors that may be linked to response.⁷ The molecular fingerprints of a tumor can be quite complex and heterogeneous, not only across tumors, but also within a single patient. Consequently, molecular tumor characterization requires both multidimensional data from laboratory and imaging tests and advanced software and computational methods for analyzing these data.⁸ This emergence of computational precision oncology is associated with both opportunities and challenges, from validation and translation to regulatory oversight and reimbursement.

Navigating the evolving regulatory landscape
The regulatory landscape is evolving to keep pace with technological advances in cell engineering and gene editing. Since 2013, the FDA has published four guidance documents on cellular and gene therapy products, as well as two guidance documents providing recommendations on regenerative medicine advanced therapies (RMATs). Specifically, their Expedited Programs for Regenerative Medicine Therapies for Serious Conditions, published in November 2017, provides guidance on the expedited development and review of regenerative medicine therapies for serious or life-threatening diseases and conditions. This document also provides information on the use of the accelerated approval pathway for therapies that have been granted the RMAT designation.⁹

In the EU, the European Medicines Agency (EMA) published a draft revision of its Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells in July 2018.¹⁰ This draft revision includes current thinking on the requirements for nonclinical and clinical studies, as well as specific sections on the scientific principles and clinical aspects of CAR-T products.

Overcoming manufacturing challenges
Precision medicines such as CAR-T therapies require manufacturers to transform a complex, individualized treatment into a commercial product. In conventional manufacturing, the entire manufacturing process occurs within the confines of the manufacturing facility. With cell therapies, however, the process begins with the collection of cells from the patient and ends with administration of the final product (see Figure 2 in the slider above). In between, the cells are handed off multiple times for the process of genetic modification, creating a complex supply chain that blends manufacturing and administration.¹¹

Moreover, in contrast to traditional manufacturing where the starting materials are standardized or well-defined, the starting materials for cell therapies are derived from patients and, thus, highly variable.

As evidenced by the manufacturing challenges that plagued the launch of Kymriah (tisagenlecleucel), even pharmaceutical giants have struggled with meeting label specifications for commercial use.¹³ To help address its manufacturing hurdles, Novartis acquired CellforCure, a contract development manufacturing organization, and plans to transform by focusing on data and digital technologies.^14,15 What this means for sponsors is that robust, scalable manufacturing must be incorporated into clinical developing planning at its earliest stages.

Improving access with new pricing models
The high price tags associated with CAR-T therapies illustrate how expensive targeted therapies are in comparison to their traditional counterparts.¹⁶ Existing health insurance models have not been structured to reimburse for costly treatments that offer the potential for long-term benefit or even cure. The pricing model for CAR-T therapies may be especially challenging for private insurance companies, which have higher turnover and shorter coverage windows than national health insurance programs. For sponsors of precision medicine therapies, one way to address the challenge of reimbursement is to create innovative, value- or outcomes-based pricing models, rather than focusing on sales volume. The success of these new pricing models will rely on patient selection. To demonstrate value and optimizing outcomes, sponsors will need to develop profiles of patients who are most likely to respond and provide tools for identifying these patients.⁸

Of note, on August 7, 2019, the Centers for Medicare & Medicaid Services (CMS) finalized the decision to cover FDA-approved CAR-T therapies when provided in healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS) for FDA-approved indications. Medicare will also cover FDA-approved CAR-T treatments for off-label uses that are recommended by CMS-approved compendia.¹⁷

Partnering with other stakeholders
Beyond the pharmaceutical companies that are working to develop personalized treatments, the precision medicine ecosystem has a number of other key stakeholders—regulators, payers, diagnostic companies, healthcare technology companies, healthcare providers and, of course, patients. Pharmaceutical companies need to engage with each of these stakeholders by providing education or developing partnerships that help demonstrate the need for high-quality data collection, the value of precision medicine, and the process for identifying the right patients.

Sponsors may also benefit from engaging with patient advocacy groups as these groups play a critical role in connecting patients and caregivers with scientific and healthcare experts to learn about how new immunotherapy breakthroughs are changing the standard of care. 

Reaching the pinnacle of precision medicine
Empowered patients pushing for the latest innovations are propelling precision medicine forward, but we still have a way to go before the full potential of precision medicine is realized. In its maturity, precision medicine will not only enable the personalization of treatments for individual patients, but also inform public health at a population level as insights from the genetic and molecular data collected are used to advance our understanding of disease. Robust data collection and analysis, along with standardization, are required for building this foundation of precision medicine, and multi-stakeholder buy-in is necessary for addressing issues around data integration and privacy.

While significant challenges remain, the opportunity to transform patient outcomes and population health with precision medicine is tantalizing. Increasingly, we are seeing advanced technologies—such as artificial intelligence and machine learning—being incorporated into the drug discovery and development process. This underscores the critical need for a multidisciplinary approach to precision medicine, from discovery at the bench all the way through to delivery at the bedside, to help ensure that more patients can access the right therapy at the right time, and the right price. 

References

1. Reuters. At 10.7% growth, Precision Medicine Market will cross $96.6 billion by 2024. Available at https://www.reuters.com/brandfeatures/venture-capital/article?id=65658
2. Cancer Therapy Advisor. Understanding the Limitations of CAR-T Cell Therapies. Available at https://www.cancertherapyadvisor.com/home/cancer-topics/hematologic-cancers/cart-cell-therapy-cancer-limitations-treatment/
3. Ventola CL. Cancer Immunotherapy, Part 1: Current Strategies and Agents. PT 2017/42(6):375-383.
4. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39(1):1-10.
5. Zugazagoitia J, et al. Current challenges in cancer treatment. Clin Ther 2016;38(7):1551-1566.
6. Mukherjee S. Genomics-Guided
7. Tsimberidou AM, et al. Defining, Identifying, and Understanding “Exceptional Responders” in Oncology Using the Tools of Precision Medicine. Cancer J 2019;25(4):296-299.
8. Improving Cancer Diagnosis and Care: Clinical Application of Computational Methods in Precision Oncology: Proceedings of a Workshop. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Care Services; National Cancer Policy Forum; Nass SJ, Patlak M, Zevon E, editors. Washington (DC): National Academies Press (US); June 2019.
9. .S. Food and Drug Administration. Expedited Programs for Regenerative Medicine Therapies for Serious Conditions: Draft Guidance for Industry. Available at https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585414.pdf
10. European Medicines Agency. Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells. Available at https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clinical-aspects-medicinal-products-containing-genetically_en.pdf
11. Genetic Engineering & Biotechnology News. Cell Therapy Manufacturing: The Supply Chain Challenge. Available at https://www.genengnews.com/insights/cell-therapy-manufacturing-the-supply-chain-challenge/
12. Hucks G, Rheingold SR. The journey to CAR T cell therapy: the pediatric and young adult experience with relapsed or refractory B-ALL. Blood Cancer J. 2019;9(2):10.
13. Biopharma Dive. In CAR-T, manufacturing a hurdle Novartis has yet to clear. Available at https://www.biopharmadive.com/news/in-car-t-manufacturing-a-hurdle-novartis-has-yet-to-clear/543624/
14. Biopharma Reporter. Novartis makes acquisition to buildout CAR-T capabilities. Available at https://www.biopharma-reporter.com/Article/2019/01/02/Novartis-acquires-CellforCure-to-boost-CAR-T-manufacturing
15. Biopharma Reporter. How to solve a problem like Kymriah. Available at https://www.biopharma-reporter.com/Article/2019/02/22/Novartis-and-digital-manufacturing-transformation
16. Blue Latitude Health. Precision Medicine from Concept to Clinic. Available at https://www.bluelatitude.com/how-we-think/precision-medicine-from-concept-to-clinic/
17. Centers for Medicare & Medicaid Services. Trump Administration Makes CAR T-Cell Cancer Therapy Available to Medicare Beneficiaries Nationwide. Available at https://www.cms.gov/newsroom/press-releases/trump-administration-makes-car-t-cell-cancer-therapy-available-medicare-beneficiaries-nationwide

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Peter Larson is the executive medical director for hematology-oncology at Premier Research.