Mark Dudley, PhD

Personalized medicine has been a rapidly growing field in the healthcare sector, but what does that mean for clinical trials? Since this therapy is typically specific to one person, the processes need to be handled carefully, and personnel need to be highly trained and diligent to ensure that the correct therapy is going to the right patient. However, this is just one aspect of the careful coordination required for a clinical trial with personalized medicine.

Adaptimmune is currently developing and investigating a type of personalized medicine known as T-cell therapy in multiple clinical trials. This type of cell therapy leverages an individual’s own immune system to fight cancer. The company engineers T-cell receptors to target solid tumors, which are inserted into a patient’s own T-cells to arm them to identify and kill cancer.

The autologous cell therapies developed by Adaptimmune, called SPEAR (specific peptide enhanced affinity receptor) T-cells, start with the collection of leukocytes (white blood cells) from patients who are undergoing treatment for various cancers. The cells are collected in a clinical setting via a process called apheresis and then shipped to a centralized manufacturing site. The T-cells are then isolated from the apheresis collection starting material, genetically modified with the SPEAR T‑cell platform, and expanded in cell culture to produce SPEAR T-cells.

Adaptimmune is committed to providing safe and effective cell therapies to patients. The company tests every SPEAR T-cell therapy rigorously to meet specifications for identity, sterility, potency, and dose. These SPEAR T-cells, with enhanced functionality to recognize and attack solid tumors, are then infused back into the patient.

The development lifecycle of SPEAR T-cell therapies shares many common features with that of biologics and other complex pharmaceuticals. Autologous T-cell therapies have some unique challenges and opportunities during clinical development, though. In early-stage development, all first-in-human studies focus on establishing safety and defining an effective dose. T-cell therapies add a new twist to early-phase trials because the engineered T-cells can rapidly expand after infusion and persist in the patient’s immune system, enabling the engineered T-cells to persist for years.

In early-stage clinical trials with T-cell therapies, dose escalation designs are often employed that balance risk of unknown adverse events with the possibility of achieving anti-tumor efficacy. Each patient provides a new window into critical quality attributes of the product that correlate with T-cell engraftment, persistence, and anti-tumor effects. Very few therapeutic approaches have evolved as rapidly as autologous T-cell therapies, because a new product lot is manufactured for each patient. As the product profile becomes better defined, the manufacturing and treatment protocols can be changed and adjusted to improve efficiency. To account for this continuous improvement, it is common for investigational new drug (IND) applications of cell therapies to have many more amendments than other more traditional products. The opportunities for rapid learning, and rapid product improvement, are unique to this personalized approach.

As Adaptimmune moves T-cell therapies into late-stage testing, the manufactured product becomes tuned for efficacy, innovation focuses on scaling the supply and distribution to large populations, and the company works to optimize the patient journey to integrate with these therapies unique product manufacturing. Adaptimmune is constantly looking to improve SPEAR T-cell therapies in both early- and late-stages of product development.

In early-stage development, the company is looking to improve its therapies in a number of ways, including:

Manufacturing engineered T-cells specific for cancer targets using a patient’s own T-cells.

 Adaptimmune genetically modifies each patient’s T-cells with a highly engineered T-cell receptor that optimally engages a tumor antigen and is intended to ensure product potency and safety.

Minimizing variability between product lots. 

The apheresis starting material for T-cell therapies is highly variable between patients. Diversity in T-cells with the apheresis reflects inherent patient genetic variability, different immune system challenges during the patient’s life, and receipt of different lymphotoxic cancer therapies prior to enrolment in a T-cell therapy protocol. T-cell selection from apheresis starting material for manufacturing and sophisticated in-process testing help to minimize the impact of variability in the apheresis material.

Optimizing an efficient manufacturing process.

 Use of automation, electronic data capture, and closed manufacturing systems are being tested and implemented to make the current good manufacturing practice (cGMP) activities faster, more reliable, and less labor intensive.

Employing state-of-the-art analytic capabilities.

 Optimized analytics enable rapid product characterization. Identification of critical quality attributes of T-cell products is used to tweak key process parameters.

Correlating product attributes with clinical outcomes.

 Cytokine levels in patient serum, dynamics of T-cell persistence after transfer, and single-cell T-cell analysis of phenotype and function for persistent cells are routinely measured. Gene expression patterns, cell surface expression of proteins, and trafficking attributes of T-cell populations are evaluated to identify correlates of effective anti-tumor therapy.

Identifying new approaches for treating solid tumors. 

Deep understanding of the mechanism of T-cell efficacy and the attributes of potent T-cell products can be translated into better products, and then investigated in small cohort clinical trials, which are focused on obtaining efficacy and safety data quickly.

Investigating next-generation T-cell products, such as those with multiple genes.

 In addition to the SPEAR T-cell receptor alpha and beta genes, the CD8alpha co-receptor gene can be introduced to autologous T-cell products. For example, ADP-A2M4CD8 is being used in the SURPASS trial to engage the patient’s CD4+ T-cell compartment, which is intended to enhance therapeutic potential.

 The impact of combined immunotherapy will be evaluated. Adaptimmune will initiate a Phase II trial combining ADP-A2M4 with pembrolizumab (SPEARHEAD-2) in patients with advanced head and neck squamous cell carcinoma. This will be the first time a SPEAR T-cell drug is used in sequence with first-line systemic therapy, namely ADP-A2M4 SPEAR T-cells and a PD-1 inhibitor. Adaptimmune has reported data showing that PD-L1 upregulation in response to SPEAR T-cell tumor infiltration and activity may represent a mechanism of resistance (SITC 2019).

As the company’s products enter late-phase clinical trials, including registration trials for filing biological license applications (BLAs), other types of innovations are being explored, with some aimed at generating manufacturing and delivery systems for scalable global supply. Two areas of focus for Adaptimmune are: ensuring a robust chain of custody and chain of identity and optimizing cold-chain logistics.

A key priority for Adaptimmune is the patient experience, including minimizing the time between identifying an eligible patient and delivering their autologous cell therapy for infusion. Opportunities for new technologies for improved speed and reliability are seen in logistics and supply chain, managing lymphocyte collection at apheresis sites, scheduling manufacturing slots at the centralized manufacturing facility, and ensuring capacity at treating hospital centers.

Adaptimmune has partnered with Vineti, a provider of supply chain software with a personalized therapy management (PTM) platform. Investment in bespoke software solutions for unique challenges with patient scheduling, product tracking, and patient sample management ensures scalability, while maintaining the standards of quality and regulatory compliance. Similarly, Adaptimmune is investing in development of manufacturing execution systems and enterprise resource planning software to ensure optimization of production as the company moves closer toward a commercial product.

Decreasing the time for manufacturing and simplifying the release testing is very important to improving the patient experience. Additional innovation will allow patients and physicians to engage with the production of the autologous therapy and follow the “cell journey” during the transformation from apheresis product to final product. Similarly, an opportunity exists to explore performing patient therapy steps outside of traditional clinical centers to bring autologous T-cell therapies closer to patients. While there are many advantages to a centralized manufacturing model, and to a high-volume clinical treatment facility, there are also opportunities to bring apheresis and follow-up services closer to the patient’s home. The COVID-19 pandemic has magnified the impact and value of such distributed approaches for many aspects of healthcare delivery. Adaptimmune is evaluating approaches that simplify the patient experience, decrease risks of travel, and increase visibility for physicians and patients.

In early-stage development, flexibility is a key factor and “speed to success” strategies allow exploration of many approaches to get to the best product. Adaptimmune’s decision to build a fully integrated cell therapy company, with a range of in-house capabilities, enables it to identify innovations and adjust processes quickly. The company’s in-house manufacturing capabilities allow it to transition from an exploratory development stage to one focused on supply and distribution—ultimately leading to more effective products that can be delivered more efficiently to patients with cancer.

Success in cell therapies targeting solid tumors will progress rapidly as the field gains experience. Many solid tumors remain difficult to treat, thus requiring new and improved approaches. Adaptimmune is applying what it learns via translational sciences to better understand the attributes of individual cancers and their interaction with the immune system. As a result, T-cell therapies can be targeted appropriately, and persist in patients, while overcoming tumor microenvironment and resistance mechanisms that are unique to each cancer. Developing these therapies with constant reference to the patient and physician experience is key.

The future of cell therapies in the clinic

Autologous therapies have the potential to change cancer treatment as we know it. Adaptimmune has been working in autologous cell therapies over the past decade, and the positive results it has seen in clinical trials have been encouraging. The company initiated a Phase II trial, SPEARHEAD-1, in synovial sarcoma and myxoid/round cell liposarcoma, which it believes could be used for registration as the company aims to make its first therapy available in the U.S. in 2022. In addition, this year at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting, Adaptimmune reported responses in multiple solid tumor types, including sarcoma, esophagogastric junction (EJG), head and neck, and lung cancers with its first-generation ADP-A2M4 SPEAR T-cells and next-generation therapy ADP-A2M4CD8 SPEAR T-cells. Based on early promising data in EJG cancer, Adaptimmune plans to start another Phase II trial next year with ADP-A2M4CD8.

These therapies can be given to any patient and do not depend on making modified cell products from each individual patient’s cells. This type of platform derives universally acceptable immune cells from stem cells and could completely change the patient experience by delivering “off-the shelf” cell therapies.

Adaptimmune has been developing an allogeneic platform and recently presented findings at the 2020 American Society of Gene &Cell Therapy (ASGCT) Annual Meeting. Data presented summarized recent advances in Adaptimmune’s allogeneic platform, demonstrating the production of engineered T-cells, differentiated from human induced pluripotent stem cells (hiPSC) (iT cells). These findings suggest that, like autologous SPEAR T-cells currently in clinical trials, Adaptimmune’s ADP-A2M4 iT-cells have the potential to be an efficacious cell therapy.

Allogeneic products are often referred to as “on-demand” or “off-the-shelf,” in contrast to autologous products that are manufactured 

 for each patient. The possibility of manufacturing in advance of demand allows storage and stocking of the therapeutic agent. Eventually, this could mean that these products could be used in community hospitals instead of restricting treatment to larger academic centers, as is the case with autologous cell therapy now. The time it takes to access treatment is critically important to people with cancer at all stages of diagnosis—making fast delivery of treatment a key priority for all cell therapies.

Adaptimmune is committed to building on its preclinical testing expertise and the clinical success of its autologous therapies to direct the evolution of its stem cell-derived allogeneic platform. Both autologous and allogeneic cell therapies are important in the fight against cancer. Working on both platforms simultaneously allows the translational learnings from autologous SPEAR T-cell clinical trials to be applied to the development of new SPEAR T-cell products and new platforms such as allogeneic—with the aim to speed the generation of more accessible treatments for people with cancer.

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