...T cells that target tumor neoantigens arising from cancer mutations are the main mediators of many effective cancer immunotherapies in humans.Eric Tran, Paul F. Robbins & Steven A. RosenbergNature Immunology (2017)
Immuno-oncology: Neo-Antigens in Cancer
Immuno-oncology (I-O) relates to the recruitment of one’s own immune system for the treatment and eradication of cancer. Remarkable clinical results with immuno-oncology treatments within the past 5 years, in particular with immune checkpoint inhibitor drugs, have catapulted the field onto center stage for consideration by patients, clinicians, academic investigators as well as pharmaceutical and biotech companies.
The I-O premise is relatively straightforward – to unleash the killing potential due to the exquisite specificity of a patient’s T lymphocytes (predominantly CD8 T cells) to target and eliminate cancer cells throughout the body. Administration of immune checkpoint inhibitor drugs, such as monoclonal antibodies (e.g., Keytruda, Opdivo, Tecentriq) that interfere with the T cell immune restraints imposed by PD-1 : PD-L1 receptor interactions have dramatically realized the potential to yield rapid and durable clinical responses in those patients whose T cells have already been trained, yet silenced, to eliminate the tumors. These drugs, while highly effective for patients with different cancers (e.g., melanoma, lung and bladder cancers), are limited to benefit those 20-30% of patients whose immune system shows evidence of pre-existing cancer recognition.
On closer scrutiny of the T cell immune responses in patients that benefit from monotherapy treatment with immune checkpoint inhibitor drugs, significant evidence has been generated that the patients’ CD8 T cells likely target protein mutations (antigens) unique to the tumor (neo-antigens). As shown in the figures below, patients whose tumors harbored a greater collection of unique mutations (high nonsynonymous burden; neo-antigen burden) were significantly more likely to benefit clinically from immune checkpoint anti-PD-1 drug monotherapy. This means that the patients already had a collection of CD8 T cells with the ability to recognize peptides derived from these neo-antigens presented to the immune system on the HLA receptors on tumors (neo-epitopes). Since these neo-epitopes are only displayed on the surface of tumor cells, patient T cells that target neo-epitopes should only kill tumor cells. Unleashing the patients’ neo-epitope specific T cells is, therefore, likely responsible for the rapid and durable clinical benefits seen in some patients upon administration of immune checkpoint inhibitor drugs.
The PACT Approach – Synthesizing the Tsunami of Neo-Epitope Targeted T Cells (Synthetic TILs)
The next wave in immuno-oncology success will depend on initiating highly specific T cell immune recognition of cancers. Based on the current evidence, unleashing a tsunami of T cells that recognize and kill cancer cells displaying patient-specific mutations (neo-epitopes) holds great potential to significantly increase the number of cancer patients that will benefit from I-O therapies.
PACT Pharma is dedicated to synthesizing a tsunami of neo-epitope targeted T cells and producing a personalized adoptive cell therapy designed to benefit each individual cancer patient (as outlined in the diagram below). The neo-epitope targeting is engineered into the patient’s own T cells (autologous T cells) for programming to seek out, infiltrate into the tumor and kill the tumor cells displaying the unique neo-epitopes. In essence, PACT Pharma is engineering next generation synthetic tumor-infiltrating lymphocytes (synthetic TILs), tailored for each patient’s cancer with highly efficient turnaround in manufacturing from tumor biopsy to re-infusion of autologous synthetic TILs back into the patient.
We have developed a high-throughput, automated process for the cloning, expression and purification of soluble neoE-HLA proteins. We can generate neoE-HLA libraries in single production runs for up to several hundred neoE-HLA candidates per patient. These soluble neoE-HLA proteins are then assembled into barcoded “snare libraries” for the interrogation of matched PBMCs from that patient for CD8 T cells that specifically bind the cognate neoE-HLA tumor targets.
Of the 13 thousand HLA alleles in the human population, with 6 HLA alleles expressed in each person, our HLA catalog enables rapid production of neoE-HLA protein candidate libraries, representing >4 of 6 HLAs coverage for ≥95% of all patients, regardless of ethnicity. The imPACT Isolation Technology® is applied to the identification and reproducible capture of neoE-specific T cells CD8 T cells from blood and other tissues with ultra sensitivity, i.e. at frequencies of at least 1 neoE-specific T cell per 106 CD8 T cells interrogated.
Following imPACT Isolation Technology®, our machine learning algorithms define the most relevant neo-epitope (NeoE) specific CD8 T cells for therapeutic benefit, from which we extract the T cell receptor (TCR) sequences for PACT TCR-T product development. Using (non-viral) precision genome engineering, the NeoE-targeted TCR sequences replace the endogenous TCR of fresh CD8 and CD4 T cells collected from that same patient’s peripheral blood (autologous NeoE TCR engineered into autologous fresh T cells) followed by minimal expansion in preparation for re-infusion into the patient. These patient-specific TCR-T cells are formulated to immediately kill all neoantigen-expressing tumors, together with a deep reservoir of ‘ready-to-go’ TCR-T cells for long term persistence and capable of rapid expansion to prevent future cancer recurrence.
In summary, PACT Pharma is engineering autologous synthetic TILs, which, when administered into the patient, are designed as a tsunami of tumor-specific T cells capable of rapid elimination of cancer throughout the body for durable clinical benefit. This is the promise of next-generation immuno-oncology: to unleash the patient’s immune system to eradicate cancer…