Abstract LB-148: Combination treatment of the CHK1 inhibitor, SRA737, and low dose gemcitabine demonstrates profound synergy with anti-PDL1 inducing durable tumor regressions and modulating the immune microenvironment in small cell lung cancer
Bibliographic record
Abstract
Abstract Background: Small cell lung cancer (SCLC), the most aggressive form of lung cancer, shows poor response rates to immunotherapy targeting the programmed cell death protein 1 pathway (PD-(L)1). Our group previously discovered that SCLC exhibits high expression of checkpoint kinase 1 (CHK1) and that the CHK1 inhibitor SRA737 activates the innate immune STING pathway, demonstrating robust anti-tumor activity and synergy in combination with anti-PD-L1 in an SCLC model. As SRA737 is being tested in SCLC patients in combination with low dose gemcitabine (LDG), we evaluated the efficacy and immune correlates (including macrophages associated with resistance to immune checkpoint blockade) of the SRA737+LDG regimen in combination with anti-PD-L1 in an SCLC model. Results: Trp53, Rb1 and p130 (RPP) triple knockout SCLC cells were implanted into the flank of B6129F1 immunocompetent mice. After the mice developed tumors, they were treated with single agents or various drug combinations. Anti-PD-L1 and LDG demonstrated minimal effect on tumor growth as single agents and only a modest effect as a combination. Moderate to strong anti-tumor activity was however observed with SRA737 monotherapy which directly correlated with dosing intensity. The most profound and synergistic anti-tumor activity was observed when anti-PD-L1 was combined with the SRA737+LDG regimen, with all animals showing durable regressions. Analysis of tumor infiltrating immune cells at the end of this treatment regimen showed a dramatic induction of cytotoxic T-cells and a reduction of exhausted and regulatory T cells. Similarly, pro-inflammatory M1 type macrophages and dendritic cells were increased while immunosuppressive M2 type macrophages and MDSC cells were dramatically decreased. As monotherapy, the more dose intensive SRA737 schedule resulted in similar effects on lymphocytes when combined with anti-PD-L1. These effects are consistent with our previous data showing that SRA737 treatment leads to an induction of STING and type I interferon signaling in tumors, which is associated with the establishment of an anti-tumor immune microenvironment. Discussion: Our findings suggest that the combination of anti-PD-L1 with the SRA737+LDG regimen may represent the optimal implementation of these agents, leading to a dramatic anti-tumor activity accompanied by the establishment of a strong anti-tumor immune microenvironment. Given that anti-PD-(L)1 drugs are approved but show limited efficacy in SCLC, our preclinical data provide a strong rationale for combining these agents with the SRA737+LDG regimen to enhance clinical response rates. Citation Format: Triparna Sen, Carminia M. Della Corte, Snezana Milutinovic, Lixia Diao, Robert J. Cardnell, Ryan J. Hansen, Bryan Strouse, Michael P. Hedrick, Christian Hassig, Jing Wang, Lauren A. Byers. Combination treatment of the CHK1 inhibitor, SRA737, and low dose gemcitabine demonstrates profound synergy with anti-PDL1 inducing durable tumor regressions and modulating the immune microenvironment in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-148.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".