We provide both empirical and theoretical insights to demystify the gravity well phenomenon in the optimization landscape. We start from describe the problem setup and theoretical results (an escape time lower bound) of the Softmax Gravity Well (SGW) in the literature. Then we move toward the understanding of a recent observation called ASR gravity well. We provide an explanation of why normal distribution with high variance can lead to suboptimal plateaus from an energy function point of view. We also contribute to the empirical insights of curriculum learning by comparison of policy initialization by different normal distributions. Furthermore, we provide the ASR escape time lower bound to understand the ASR gravity well theoretically. Future work includes more specific modeling of the reward as a function of time and quantitative evaluation of normal distribution’s influence on policy initialization.
Abstract Immune checkpoint therapy has demonstrated durable clinical responses in multiple solid tumor types. Reduced clinical response to checkpoint therapy has been linked to the presence of potent immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment that contribute to tumor immune evasion. The transcription factor Helios (IKZF2) is a marker of highly suppressive Tregs and is required to maintain a stable, suppressive Treg cell phenotype in the inflammatory tumor microenvironment. Depletion of IKZF2 in Tregs results in both loss of suppressive activity and conversion of Tregs into effector-like T cells, leading to anti-tumor immunity. Targeted protein degradation using the endogenous Ubiquitin Proteasome System (UPS) has enabled targeting undruggable proteins, such as IKZF2, that have no known small molecule binding pocket. We have designed small molecules that promote a novel interaction between IKZF2 with the E3 ubiquitin ligase substrate receptor, Cereblon, leading to proximity induced protein degradation. PLX-4107 is a novel molecular glue that is a highly selective, potent, and rapid degrader of IKZF2 via the redirection of the E3 substrate receptor, Cereblon. Degradation of IKZF2 by PLX-4107 is blocked in the presence of proteasome and neddylation inhibitors as well as a Cereblon knock-out cell line, confirming that degradation is mediated by the UPS and specifically through the involvement of Cereblon. Proteome-wide analysis demonstrated that PLX-4107 selectively depletes IKZF2 protein levels without degrading other known Cereblon neo-substrates. In vitro, PLX-4107 mediated degradation of IKZF2 resulted in conversion of suppressive Tregs into CD4+ effector-like T cells, coupled with an increased production of the effector cytokines IL2 and IFNg. Oral administration of PLX-4107 to cynomolgus monkeys demonstrated sustained pharmacodynamic response, persistent depletion of IKZF2, and reprogramming of Tregs, consistent with the catalytic mechanism of protein degradation. In vivo, T cell expansion studies showed that administration of PLX-4107 decreased both Treg CD25 expression and proliferation, along with increased activation of CD8+ T effector cells. PLX-4107 was evaluated in in vivo xenograft efficacy studies and demonstrated dose dependent single agent anti-tumor activity that was dependent on the presence of T cells. In addition, co-administration of PLX-4107 and anti-PD-1 antibody Pembrolizumab resulted in tumor growth inhibition and significant combination benefit. PLX-4107 is a novel molecular glue that selectively degrades the undruggable transcription factor, IKZF2. PLX-4107 mediated IKZF2 degradation results in conversion of Tregs to an effector-like T cell phenotype, single agent antitumor activity and the ability to enhance the efficacy of immune checkpoint therapy in vivo. Citation Format: Peggy A Thompson, Pengyu Yang, Linette Yang, Susan Song, Yujun Huang, Xiaoming Li, Alejandro Dearie, Stephen Chien, Mary E Spalding, Gabrielle Blanco, Elizabeth Daniele, Julia Toth, Aleksandar Jamborcic, Gregory Parker, Simon Bailey. PLX-4107, a selective IKZF2 degrader, reprograms suppressive regulatory T cells and demonstrates anti-tumor activity [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B37.
Tumors avoid immunosurveillance by recruiting suppressive regulatory T-cells (Treg) limiting the activation and expansion of tumor effector T-cells (Teff). Checkpoint inhibitors (CPI) have significantly advanced cancer treatment; nevertheless, responses are limited to patient subsets. Efforts have focused on developing immune-oncology agents that regulate suppressive and dysregulated immune cells in the tumor microenvironment (TME). The transcription factor IKZF2 (Helios), a marker of highly suppressive Tregs, is required to maintain a stable Treg phenotype in the inflammatory TME and is also implicated in dysregulated tumor CD8 T-cells. PLX-4545 is a potent and selective IKZF2 degrader, designed to deplete IKZF2 and convert suppressive Tregs into effector-like T-cells leading to antitumor immunity.
Methods
Bioinformatics analysis of TCGA gene expression data was conducted to prioritize tumor types. Flow cytometry was used to profile drug effects on immune cells. Tumor resident immune cells were evaluated by immunohistochemistry. In vivo efficacy studies were conducted using humanized mice implanted with syngeneic or xenograft tumor models.
Results
Gene expression analysis identified tumor types with elevated IKZF2 expression that correlated with immune gene signatures. In vitro immune profiling of PBMCs from cancer patient vs. healthy donors were evaluated to identify potential patient selection biomarkers. Treatment of PBMCs with PLX-4545, in vitro, lead to rapid and complete degradation of IKZF2 and conversion of suppressive Tregs into effector-like T-cells. Combination with anti-PD1 significantly increased proliferation of CD4/CD8 Teff cells. In vivo efficacy studies with oral administration of PLX-4545 resulted in dose dependent depletion of IKZF2 and single agent antitumor activity. Immune profiling confirmed that IKZF2 is more highly expressed in activated Tregs in the TME. Degradation of IKZF2 with PLX-4545 treatment preferentially converted tumor Tregs into effector-like T-cells through decreased CD25 expression and increased production of effector cytokines (IL2, IFNg), resulting in increased proliferation of CD4/8 Teff cells and infiltration into tumor tissue. Combination of PLX-4545 with anti-PD1 significantly increased the proliferation of Teff cells and tumor growth inhibition in vivo.
Conclusions
IKZF2 is elevated in cancer patient subsets and correlates with Treg infiltration into the TME. PLX-4545, a potent and selective IKZF2 degrader, converts suppressive Tregs into effector-like T-cells and enhances CD8 T-cell response, resulting in single agent antitumor activity and combination benefit with CPI. PLX-4545 provides the potential to overcome immune resistance and broaden clinical response to CPI. PLX-4545 is currently in a Phase I clinical trial to evaluate safety, exposure and pharmacodynamic response.
Data on 1,281 patients from the Bilitch impIantabje cardioverter defibrillator (ICD) registry were reviewed to evaluate ICD patient characteristics and survival, and the impact of ICD shock occurrence on outcome. The mean ejection fraction was 34.3%; 78% had coronary disease, 471 patients had at least one shock thought to be appropriate, and 231 patients died. Causes of death included: arrhythmic (41%), nonarrhythmic cardiac (37%), and noncardiac (22%). Cumulative survival from all‐cause mortality at 1, 3, and 5 years was 89%, 76%, and 64%; survival from all‐cause cardiac death was 93%, 90%, and 76%; survival from arrhythmic death was 96%, 92%, and 87%. Patients who had received a shock had a trend towards a worse long‐term prognosis. Shock patients also had a small increase in the prevalence of coronary disease and a somewhat lower ejection fraction than the remainder of the population.
