October 2020 – Targeted T cell-derived therapies have shown some of the greatest promise in treatment of cancers, to date. However, most T cell-derived therapies require ex vivo manipulation of patients’ cells, a costly and technically challenging process. In a recently-published paper, researchers from Cue Biopharma demonstrated the in vitro and in vivo efficacy of novel treatment, CUE-101, in driving proliferation of antigen-specific CD8+ T cells to selectively target and suppress tumor growth.
CUE-101 was designed with immune specificity in mind, including a target epitope (common to HPV-derived tumors), and reduced-affinity domains to prevent toxicity or non-specific binding. After verifying the effectiveness of the structure of CUE-101, the molecule was applied to PBMCs from two healthy donors and evaluated for immune cell expansion.
TCR repertoire diversity of the stimulated PBMCs was examined using iRepertoire’s iPair technology. Typically, when RNA is extracted for bulk repertoire sequencing, information related to the cognate pairing of TCR chains is lost. iRepertoire’s single cell service, iPair, is the first consumer-based service specifically designed for capturing physically paired variable regions in T cells and B cells, which allowed for detailed characterization of the treated PBMCs.
iPair analysis revealed that stimulation with CUE-101 resulted in selective, concentration-dependent expansion of antigen-specific CD8+ T cells. Astonishingly, one donor’s cells expanded into multiple unique TCR clones, suggesting the treatment stimulated polyclonal populations of antigen-specific TCRs.
Next, in vivo tests showed that CUE-101 was well-tolerated, and effectively expanded antigen-specific T cells that suppressed tumor growth in mice. Combining this treatment with PD-1 blockade resulted in 60% of animals being tumor-free at 79 days post-engraftment.
Overall, CUE-101 was well-tolerated, and did not show the same toxicity effects as other commonly-used tumor treatments. Immune repertoire analysis verified that the treatment is capable of generating polyclonal, CD8+ T cell responses to tumors and was predictive of the in vivo results.
Unlike previous methods, CUE-101 requires no ex vivo manipulation of patients’ cells, and thus bypasses the cost and complications associated with such techniques, while providing the same targeted approach (as validated by immune repertoire analysis) to use a patient’s immune system to suppress tumor growth. Due to its simplicity and effectiveness in generating antigen-specific tumor suppression without cross-reaction, it is possible this method of treatment could be applied in the future to other types of cancer.
The study, which provided detailed analysis on the efficacy of CUE-101 from in vitro models that were predictive of the in vivo effects using iPair analysis, allowed the treatment to proceed quickly to use in a phase I clinical trial (NCT03978689). Ultimately, their findings suggests that iPair technology is poised to evaluate novel therapies for efficacy by determining their impact on the immune system prior to and during clinical testing.