Platform Development and Progress in Immuno-oncology
Drug candidates developed within our IL-2 based CUE-100 series are therapeutic proteins engineered from our Immuno-STAT and Neo-STAT platforms, designed to selectively engage and activate disease-relevant T cells. The core framework for the IL-2-based CUE-100 series was determined from structure-based rational protein engineering solution that incorporated Signal 1 (pMHC) and Signal 2 (modified IL-2) in an optimal spatial configuration that allows for selective and specific activation of antigen-specific T cells over the majority of irrelevant T cells. Hence, the CUE-100 series is designed to selectively deliver IL-2 to tumor-specific CD8+ T cells.
The core configuration of CUE-100 series is engineered to be symmetrical and consists of a pair of pMHC molecules that are each flanked by two molecules of engineered modified IL-2 (or IL-2 variant). Two notable structural modifications to IL-2 are important: (i) the abrogation of binding to IL-2 receptor alpha subunit eliminates bias towards induction of regulatory T cells and reduces the risk of safety liabilities such as vascular leak syndrome and broad cytokine secretion (i.e., cytokine storm); and (ii) further attenuation of binding to IL-2 receptor beta subunit ensures that the activity of IL-2 is most evident when only disease-relevant T cells are engaged to the pMHC molecules. The latter point exploits the co-operative nature of T cell activation wherein the threshold for signal strength for T cell activation is optimally achieved when both Signal 1 (pMHC engagement) and Signal 2 (modified IL-2) are received by T cell receptors (TCR) and IL-2 receptors of the same T cell. In the absence of TCR engagement, the modified IL-2 is sufficiently attenuated to minimize systemic effects on non-tumor-specific T cells, which constitute the vast majority of the T cell repertoire in a patient.
Preclinical data demonstrating the selectivity and specificity of the CUE-100 series along with mitigation of safety risks have been presented at key scientific meetings and published in Clinical Cancer Research in April 2020. See links below.
Why an IL-2 Variant?
IL-2 is a critical cytokine that acts locally in tumors and lymph nodes in a highly regulated manner to stimulate tumor-antigen specific CD8+ T cells to proliferate and eliminate tumor cells. Although the FDA-approved IL2 drug Proleukin (wild-type IL-2) is effective in a small proportion of patients (15% to 16% per its product label), it has not been widely used due to its severe dose-limiting toxicities and systemic effects. More recently, other IL-2 constructs (referred to as “not-alpha” IL-2 variants) have been developed to reduce the unwanted side-effect profile of Proleukin, but these do not provide a selective T cell targeting capability.
The CUE-100 series also possess the “not-alpha” IL-2 property but is differentiated from other “not-alpha” IL-2s in an important way: because of its conjugation to a tumor-specific pMHC, the CUE-100 series biologics preferentially activate tumor-specific CD8+ T cells. Other “not-alpha” IL-2s are indiscriminate in that they are capable of activating any T cells they encounter, which has little relevance to anti-tumor immunity and may possibly cause off-target adverse events with these unproductive interactions.
Differentiation Over Existing Modalities Targeting IL-2
CUE-101 is a novel fusion protein that incorporates HLA-A*0201 allele (the MHC portion) bound to an epitope from the HPV 16 E7 protein (E711-20) and is designed to activate and expand tumor-specific T cells that target Human Papilloma Virus 16 (HPV16)-driven malignancies.
In preclinical studies, CUE-101 demonstrated selective binding and preferential activation and expansion of E7-specific T cells, dose-dependent effector cytokine production, inhibition of tumor growth and significant prolongation of survival both as a monotherapy and in combination with an anti-PD-1 antibody (αPD1) in tumor-bearing mouse models. In addition, new tumors did not grow when surviving mice already treated with CUE-101 were re-challenged with a second injection of tumor cells, hence demonstrating induction of immunological memory. The memory was largely resident within the CD8+ T cell compartment.
The results of these preclinical studies were presented at the Society for Immunotherapy of Cancer’s (SITC) 34th Annual Meeting in November 2019 and published in Clinical Cancer Research (Clin Cancer Res April 15, 2020, 26 (8): 1953-1964; DOI:10.1158/1078-0432.CCR-19-3354). See links below.
In September 2019, we commenced our first-in-human, dose-escalation and expansion Phase 1 clinical trial of CUE-101 in second line or later patients with HPV-positive relapsed or refractory HNSCC (NCT03978689). Cue Biopharma has engaged a network of nationally recognized clinical investigators and 14 Phase 1 sites are actively recruiting patients. For information on this trial please visit the Clinical Trials section of the website. In February 2021, we also launched a dose-escalation and expansion Phase 1 clinical trial of CUE-101 in combination with pembrolizumab (KEYTRUDA®) in newly diagnosed patients with HPV-positive recurrent or metastatic head and neck squamous cell carcinoma (NCT03978689).
CUE-102 is the second clinical candidate from the CUE-100 series and incorporates a pMHC derived from the Wilms’ Tumor protein (WT1), a well-recognized onco-fetal protein that is known to be over-expressed in a number of cancers, including solid tumors and hematologic malignancies. The core modules of CUE-102 are largely shared with CUE-101 except that a nine amino acid fragment of WT1 (WT137-45) replaces the E7 peptide of CUE-101. WT1 has been ranked first amongst 75 tumor associated antigens in an effort by the National Cancer Institute to prioritize cancer antigens for therapeutic targeting.1
Development of novel modalities to target WT1 provide a significant opportunity to address high unmet medical need in WT1-positive malignancies, including acute myeloid leukemia (AML) and ovarian, endometrial, breast, lung, colorectal and pancreatic cancers.
Preclinical studies in collaboration with our partner LG Chem, Ltd. commenced in 2019. CUE-102 induced the expansion of WT137-45-specific CD8+ T cells from unprimed and primed peripheral blood mononuclear cells from healthy subjects. Compared to Proleukin™ (aldesleukin), which is a recombinant form of wild-type IL-2, CUE-102 induced the generation of significantly less proinflammatory cytokines (TNF-α, IL-6, and IFN-γ) and led to significantly less non-specific activation of immune cells. These results suggest that, like CUE-101, CUE-102 also mitigates the risk of systemic IL-2 activation.
CUE-102: Expansion and Polyfunctionality of WT1-Specific T Cells
The results of these preclinical studies were presented at the NY Academy of Sciences Frontiers of Cancer Immunotherapy symposium on May 11-12, 2020, and at the AACR Virtual Annual Meeting on June 23, 2020. See links below.
CUE-103 will leverage the CUE-100 framework and target an antigen to be selected in collaboration with LG Chem, Ltd.
CUE-100 Series Neo-STATs
For proof-of-concept, CUE-100 series Immuno-STATs and Neo-STATs (with IL-2 variants as the co-stimulatory module) incorporating the immunogenic peptides (1) phosphoprotein 65 (pp65) from cytomegalovirus (CMV) and (2) melanoma associated antigen recognized by T cells-1 (MART-1) expressed by melanoma cells were synthesized, as well as Neo-STATs incorporating an immunogenic SARS-CoV-2 peptide. Peripheral blood mononuclear cells (PMBCs) derived from subjects exposed to CMV or from melanoma patients, were treated with Immuno-STATs and Neo-STATs incorporating pp65 or MART-1, respectively. Activation and expansion of peptide specific CD8+ T cells occurred to the same extent regardless of whether an Immuno-STAT or Neo-STAT was used, indicating essentially equivalent potency in stimulating an immune response. Activation was also selective such that PMBCs from donors reactive to CMV Immuno-STAT or Neo-STAT were not reactive to MART-1 Immuno-STAT or Neo-STAT (and vice versa). A Neo-STAT with an immunogenic SARS-CoV-from 2 stimulated the proliferation of peptide-specific CD8+ T cells whereas an empty Neo-STAT, with an unoccupied peptide binding cleft, had no effect.
Neo-STATs and Immuno-STATs with the Same Antigenic Peptide Activate Peptide-Specific CD8+ T Cells to the Same Degree
- Increases R&D efficiency by reducing cost of producing clinical grade material
- Enables targeting of multiple tumor antigens, including post-translationally modified peptides and neo-antigens for personalized therapy
CUE 100 Series RDI-STATs
Viral-specific Immuno-STATs, or RDI-STATs, can be tethered to a tumor cell via binding to tumor cell-surface antigens (e.g., Trop2, PSMA, mesothelin etc.). In this manner the tumor is coated with an RDI-STAT to make it appear like a virally infected cancer cell, which can then be recognized by the anti-viral T cells that populate the host and the tumor tissue and become activated by the RDI-STAT IL-2 to kill the tumor cell.
Viral T Cell Redirection via RDI-STATs: Immuno-STAT Framework with Tumor Targeting TAA
- Harnesses a pre-existing and robust viral T cell repertoire present in high frequency
- Superior specificity: avoids systemic activation of ALL T cells
- Superior safety: minimizes cytokine release
- De-risked by CUE-101 clinical experience
1. Cheever MA, Allison JP, Ferris AS, et al. The Prioritization of Cancer Antigens: A National Cancer Institute Pilot Project for the Acceleration of Translational Research. Clin Cancer Res 15(17): 5323–5337, 2009 (doi: 10.1158/1078-0432.CCR-09-0737)