PACT Pharma, a privately held biopharmaceutical company developing transformational personalized neoantigen-specific and off-the-shelf T cell receptor (TCR)-T cell therapies for the eradication of solid tumors, published a peer-reviewed paper in Nature in collaboration with researchers at UCLA detailing groundbreaking work characterizing and differentiating the immune responses of melanoma patients treated with anti PD-1 immunotherapy.
Researchers showed that patients who benefitted from anti-PD-1 treatment generated a diverse (polyclonal) repertoire of T cells that recognized a small group of immunodominant mutations in their tumor. These immune responses expanded and evolved in the tumor and in the peripheral blood throughout treatment. Patients who did not respond to anti-PD-1 therapy also harbored T cells that recognized their tumor-specific mutations, but their immune responses were less diverse (monoclonal) and did not expand during treatment. These first-of-their-kind findings not only provide critical understanding into differentiated patient responses to treatment, but also offer insight into strategies for potentially designing novel T cell therapies and diagnostics.
"These study findings are exciting as they show the unique, patient-specific manner in which T cell responses take shape and impact disease. This new insight has broad implications on how we think about T cell responses and how we might be able to manipulate these responses to achieve desired therapeutic outcomes," said Stefanie Mandl, Ph.D., chief scientific officer, PACT Pharma.
To conduct this first-of-its-kind research, the investigators utilized two of PACT's core platform technologies:
First, the company's ImPACT Isolation Technology® was used to isolate mutation-reactive T cells from patients' blood and tumor samples. It is important to note that blood proved equally adept in assessing tumor-specific T cell responses as tumor biopsies, underscoring the relevance of blood as a minimally invasive source for the isolation of tumor targeting TCRs and monitoring tumor-mutation specific T cell responses.
Next, investigators leveraged the company's PACT^NV™ technology to generate tumor-specific TCR-T cells using CRISPR gene replacement so that they would express the mutation-reactive T cell receptors that were isolated from patients treated with PD-1 blockade therapy. The engineered T cells were then expanded to large numbers and used by investigators to functionally characterize each individual patient's immune responses.
The study was conducted in eleven patients with metastatic melanoma. The results showed that the T cells engineered to express a specific patients' isolated TCRs were able to guide an attack on that same patients' tumor cells. This was true regardless of whether the patient responded to treatment or not. This shows that those patients who do not respond to anti-PD-1 therapy do have T cells that can recognize and kill their own tumor cells, they are just not doing so in a diverse and expansive enough manner. Based on this finding, these patients could benefit from personalized adoptive cell therapy in which their tumor-specific TCRs are isolated and then used to engineer large numbers of T cells capable of directing more effective immune responses against their own tumor.
"While this particular study was conducted in patients with metastatic melanoma treated with anti-PD-1 therapy, it provides a framework for our core platforms to be deployed for studying the mechanism of action and related patient responses for immuno-oncology therapies, vaccines and across a range of T cell-related diseases," said Dr. Mandl. "This important advance further supports the learnings from our Phase 1 clinical trial using our same proprietary TCR-T cell technologies for the development of personalized therapies for the treatment of patients with cancer, the findings of which were also published in Nature late last year. Taken together, these studies and their respective papers offer a glimpse into the potential power of technologies that enable us to push the boundaries of analyzing TCR-T cell responses and developing personalized TCR-T cell therapeutics."
A copy of the newly published Nature article, entitled, "Neoantigen-targeted CD8+ T-cell responses with PD-1 blockade therapy," can be accessed at: https://www.nature.com/articles/s41586-023-05787-1
A copy of the previously published Nature paper reporting the results of PACT's Phase 1 trial can be accessed at: https://www.nature.com/articles/s41586-022-05531-1.
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