Researchers have, for the first time, presented data demonstrating the ability to identify mutation targets unique to each person’s cancer and verify the cancer specificity of multiple cloned T-cell receptors.
The researchers found that a patient’s cancer has a ‘private’ signature of mutations. This ‘signature’ allowed them to develop fully personalized immune therapies that have the potential to eradicate tumor cells.
Defining these cancer mutation targets for each person, known as neoantigens, made it possible for researchers at PACT Pharma and their collaborators at the University of California, Los Angeles (UCLA), to develop a proprietary gene engineering technology that allowed them to manufacture an immune cell therapy product for each person with cancer.
During the Special Conference on Immune Cell Therapies for Cancer, organized by the American Association for Cancer Research (AACR), held July 19–22, 2019 in the Hyatt Regency San Francisco, San Francisco, California, researcher presented data that established the approach for verifying patient-specific cancer mutation target.
Based on the pre-clinical study results, the company has begun enrolling patients with advanced solid tumors in its first-in-human Phase I dose escalation study of NeoTCR-P1, an autologous gene-edited TCR T cell product that targets personalized neoantigens, at several key academic centers of the CIRM-funded Alpha Clinic network, in California.
Engineered NeoTCR-P1 cells are highly polyfunctional. These cells rapidly expand, secrete effector molecules including perforin (a protein, released by killer cells of the immune system, which destroys targeted cells by creating lesions like pores in their membranes) and granzyme B (a cytotoxic serum protease protein that participates in inducing apoptosis of target cells for NK Cells and cytotoxic CD8+ lymphocytes which are part of the innate immune system), and cytokines such as interferon-gamma (IFN-γ), IL-2 and TNF-alpha (TNF-α).
A bold new approach
“These exciting results open a bold new frontier for directing a person’s own immune system to treat patients with solid cancers, an area that hasn’t yet seen the successes of immune cell therapies that we have seen for blood cancers,” noted Alex Franzusoff, Ph.D., Chief Executive Officer at PACT Pharma.
“While it is early, the results demonstrate the possibility for PACT’s approach to ignite a patient’s immune response directly against their unique tumor mutation signature, within a clinically relevant time-frame, with potential applicability to most cancers and all ethnicities across the globe.”
The data presented during the AACR’s Special Conference on Immune Cell Therapies for Cancer is relevant because they show that mutations that build up in tumors, creating the unique tumor mutation ‘signature.’
This unique signature drives each patient’s cancer and has, at a very low level, already triggered each person’s immune system to target those unique mutations. Those low-level targeted immune responses can be analyzed with greater accuracy. And the result of the analysis can be used to manufacture a truly personalized treatment that is tailored for each patient with cancer.
PACT Pharma’s approach is designed to select and confirm tumor-exclusive mutations to empower a patient’s immune system to target their specific cancer. The company utilizes bioinformatics to identify the mutation blueprint of each person’s tumor, and then uses its barcoded snare technologies to capture pre-existing T-cells from the blood that already recognize and target the unique mutations.
From that group, a proprietary selection platform is used to identify the ideal T cell receptors for specific mutations. Once the target is authenticated, the company uses non-viral gene editing to engineer the ideal mutation-targeted T cell receptors into T cells from the same patient. When re-infused back to the patient, these T cells have the potential to eliminate tumor cells that express these unique mutations.
“The results presented show that the approach of neoantigen-specific T-cell capture and non-viral precision genome engineering is really groundbreaking and promising for a new chapter in personalized immune cell therapies for patients with solid cancers,” explained Antoni Ribas, a professor of medicine at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who is a co-author of the study and a co-founder of PACT.
“The demonstration that T cell receptor-engineered T cells using the PACT approach can specifically kill that same person’s cancer cells is based on the analysis of immune cells captured from the blood of a patient with a long-lasting response to anti-PD-1 therapy.”
Recently, a new generation of personalized cellular therapies for cancer has emerged. Rapid sequencing technologies, bioinformatics, and genetic/cellular engineering — in addition to a deeper understanding of clinical immunology and a renaissance in immunotherapy — have made these advancements possible. Designer immune-oncology treatments have been developed, including CAR-T cell therapies, cancer vaccines and tumor-infiltrating lymphocyte (TIL) therapies.
While transformative, these therapeutic approaches face limitations. CAR-T cells only recognize shared cancer targets expressed on the cell surface, which, while effective for blood cancers, have not been applied successfully to patients with solid cancers, and cancer vaccines are often too slow to address a rapidly growing tumor burden.
Also, tumor-infiltrating lymphocytes (TILs) can be impractical—and at times even impossible—to generate for every patient due to the difficulty of isolating limited numbers of specific tumor-targeting immune cells and then needing to greatly expand their numbers for patient dosing. In the case of expanded immune cells in particular, they often become exhausted before reinfusion, which may limit their value for eliminating the cancer throughout the body.
In order to truly tailor cancer treatments to individuals, the therapy must target each patient’s unique cancer signature, including different tissue compatibility receptors of the immune system, or HLA. These HLA receptors are key to immune recognition. This is one of the mechanisms limiting organ sharing between people. The approach, scientists at PACT Pharma, captures this nuance.
In addition, the approach is designed to select and authenticate tumor-exclusive mutations to empower the patient’s immune system to target their specific cancer for a lasting effect.
A Study of Gene Edited Autologous Neoantigen Targeted TCR T Cells With or Without Anti-PD-1 in Patients With Solid Tumors – NCT03970382
 Sennino B, Conroy A, Purandare B, Litterman A, Jacoby K, Moot R, Lu W, NguyenD, et al. NeoTCR-P1, a novel neoepitope-specific adoptive cell therapy, consists of T cells with ‘younger’ phenotypes that rapidly proliferate and kill target cells upon recognition of cognate antigen (Abstract 1433). Cancer Res July 1 2019 (79) (13 Supplement) 1433; DOI: 10.1158/1538-7445.SABCS18-1433 [Abstracts]