Emile Youssef

Precision oncology promises a new model of cancer care where medical decisions are based on a holistic view of the patient, including their genes, environment, and lifestyle, and tailored to the molecular profile of their tumor. To date, great strides toward the paradigm of precision oncology have been made in the area of cancer immunotherapy, which boosts a patient’s own immunity to combat tumor cells. Immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapies have dramatically improved outcomes for a select number of patients, but widespread use of these treatments remains elusive.

	To make personalized cancer treatment a reality for all patients, we need to reimagine the biopharmaceutical business model and drug development process, both of which have traditionally been focused on broad drug development and blockbuster medicines. New regulatory, technical, clinical, and economic frameworks are needed to ensure that the right patient can access the right therapy in a meaningful timeframe. In this article, I discuss three key challenges that must be addressed to fulfill the promise of precision oncology.

	#1: Understanding and addressing mechanisms of resistance

	The ultimate goal of cancer immunotherapy is to stimulate the immune system to launch a sustained attack against tumor cells.

 Given the complex and dynamic interactions between tumors and the immune system, achieving this is complicated.

	The challenge lies in managing the delicate balance between autoimmunity and the immune system’s ability to recognize non-self. 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 myriad methods for evading the immune system (see Figure 1 below).

	Resistance to cancer immunotherapy can be categorized as primary (i.e., failure to respond) or secondary (i.e., relapse after successful treatment). Approaches for optimizing response and minimizing resistance to cancer immunotherapies include developing biomarkers to assist with patient selection or treatment monitoring, 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 after infusion or due to antigen loss of the target receptor.

	Given the elaborate interplay between cancer and immunity, combination therapies may be a rational approach to addressing resistance. For example:

		Combining two immunotherapies targeting distinct immune checkpoints (see Figure 1).

		Combining an immunotherapy with chemotherapy, which directly kills tumor cells and may help activate the immune system to boost the response to immunotherapy.

		Combining an immunotherapy with targeted therapy to create a possible synergistic effect.

	#2: Solving the logistics of manufacturing

	Whereas the conventional manufacturing process is typically confined to a single facility, manufacturing of cell therapies requires multiple hand-offs. While the process begins and ends at the bedside, the process of genetic modification involves a complex chain of custody that blends manufacturing and administration (see Figure 2).

 The manufacturing process is further complicated by the fact that, unlike traditional manufacturing where the starting materials are standardized, the starting materials for cell therapies are highly variable because they are derived from patients.

As evidenced by the highly publicized manufacturing hurdles surrounding the launch of Kymriah (tisagenlecleucel), meeting label specifications for commercial use is challenging, even for industry leaders.

 Sponsors must consider how manufacturing will evolve from a single center or investigator-initiated trial to a multi-site commercial endeavor. Proactive planning around logistics is also critical, and the sponsor will need to create an infrastructure for tackling and managing all aspects of chain of custody in a highly controlled manner.

	#3: Developing innovative pricing models

	Targeted therapies are quite costly in comparison to their traditional counterparts, and existing health insurance models have not been structured to reimburse for these types of treatments.

 The pricing model for CAR-T therapies may be especially challenging for commercial insurers, which typically have higher turnover and shorter coverage windows than national health insurance programs. Value- or outcomes-based pricing models represent one approach to addressing the challenge of reimbursement. These new pricing models will rely heavily on patient selection, and sponsors will need to develop tools for identifying those patients who are most likely to respond to particular precision medicines.

	Notably, the Centers for Medicare & Medicaid Services (CMS) recently finalized their decision to cover FDA-approved CAR-T therapies when provided in healthcare facilities enrolled in 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.

	Realizing the promise of precision oncology

	The precision medicine market is expected to exceed $96 billion by 2024, with the oncology segment leading the way.

 Patients, providers, and advocacy groups are pushing for innovation, but precision oncology is still in its infancy and significant challenges remain. As advanced technologies and data analytic techniques are increasingly incorporated into the drug discovery and development process, the hope is that precision oncology will not only enable the personalization of cancer drugs, but also improve population health as new genetic and molecular insights enhance our understanding of the mechanisms of disease.

		Ventola CL. Cancer Immunotherapy, Part 1: Current Strategies and Agents. 

		Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. 

		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/

		Hucks G, Rheingold SR. The journey to CAR T cell therapy: the pediatric and young adult experience with relapsed or refractory B-ALL. 

		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/

		Blue Latitude Health. Precision Medicine from Concept to Clinic. Available at 

https://www.bluelatitude.com/how-we-think/precision-medicine-from-concept-to-clinic/

		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

		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

 MD, PhD, is the Executive Medical Director, Oncology at Premier Research

Articles

Outlining the three critical challenges that need to be addressed to make personalized cancer treatment a reality.

The Challenges in Fulfilling the Promise of Precision Oncology

	Precision oncology promises a new model of cancer care where medical decisions are based on a holistic view of the patient, including their genes, environment, and lifestyle, and tailored to the molecular profile of their tumor. To date, great strides toward the paradigm of precision oncology have been made in the area of cancer immunotherapy, which boosts a patient’s own immunity to combat tumor cells. Immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapies have dramatically improved outcomes for a select number of patients, but widespread use of these treatments remains elusive. 

	To make personalized cancer treatment a reality for all patients, we need to reimagine the biopharmaceutical business model and drug development process, both of which have traditionally been focused on broad drug development and blockbuster drugs. New regulatory, technical, clinical, and economic frameworks are needed to ensure that the right patient can access the right therapy in a meaningful timeframe. In this article, I discuss three key challenges which must be addressed to fulfill the promise of precision oncology.

	#1 Understanding and addressing mechanisms of resistance

 Given the complex and dynamic interactions between tumors and the immune system, achieving this is complicated. The challenge lies in managing the delicate balance between autoimmunity and the immune system’s ability to recognize non-self. 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 myriad methods for evading the immune system (see Figure 1).

	Resistance to cancer immunotherapy can be categorized as primary (i.e., failure to respond) or secondary (i.e., relapse after successful treatment). Approaches for optimizing response and minimizing resistance to cancer immunotherapies include developing biomarkers to assist with patient selection or treatment monitoring, 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 after infusion or due to antigen loss of the target receptor. 

		Combining two immunotherapies targeting distinct immune checkpoints (see Figure 1)

		Combining an immunotherapy with chemotherapy, which directly kills tumor cells and may help activate the immune system to boost the response to immunotherapy

		Combining an immunotherapy with targeted therapy to create a possible synergistic effect

Figure 1. Potential Immunotherapy Targets

Figure Source: Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39(1):1-10.

	#2 Solving the logistics of manufacturing

 The manufacturing process is further complicated by the fact that, unlike traditional manufacturing where the starting materials are standardized, the starting materials for cell therapies are highly variable because they are derived from patients.

Figure Source: 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.

	As evidenced by the highly publicized manufacturing hurdles surrounding the launch of Kymriah (tisagenlecleucel), meeting label specifications for commercial use is challenging, even for industry leaders.

Sponsors must consider how manufacturing will evolve from a single center or investigator-initiated trial to a multi-site commercial endeavor. Proactive planning around logistics is also critical, and the sponsor will need to create an infrastructure for tackling and managing all aspects of chain of custody in a highly controlled manner.

 The pricing model for CAR-T therapies may be especially challenging for commercial insurers, which typically have higher turnover and shorter coverage windows than national health insurance programs. Value- or outcomes-based pricing models represent one approach for addressing the challenge of reimbursement. These new pricing models will rely heavily on patient selection, and sponsors will need to develop tools for identifying those patients who are most likely to respond to particular precision medicines.

	Notably, the Centers for Medicare & Medicaid Services (CMS) recently finalized their 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.

	The precision medicine market is expected to exceed $96 billion by 2024, with the oncology segment of the market leading the way.

 Patients, providers, and advocacy groups are pushing for innovation, but precision oncology is still in its infancy and significant challenges remain. As advanced technologies and data analytic techniques are increasingly incorporated into the drug discovery and development process, the hope is that precision oncology will not only enable the personalization of cancer treatment, but also improve population health as new genetic and molecular insights enhance our understanding of the mechanisms of disease. 

, MD, PhD is the Executive Medical Director, Oncology at Premier Research.

		Ventola CL. Cancer Immunotherapy, Part 1: Current Strategies and Agents. PT 2017/42(6):375-383.	

		Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39(1):1-10.	