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Combination Therapy with T Cell Engager and PD-L1 Blockade Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2020-001141 on 27 August 2020. Downloaded from Combination therapy with T cell engager and PD- L1 blockade enhances the antitumor potency of T cells as predicted by a QSP model 1 1 1 2 2 Huilin Ma , Hanwen Wang, Richard J Sové, Jun Wang, Craig Giragossian, Aleksander S Popel1,3 To cite: Ma H, Wang H, Sové RJ, ABSTRACT BACKGROUND et al. Combination therapy Background T cells have been recognized as core Colorectal cancer (CRC), especially meta- with T cell engager and PD- effectors for cancer immunotherapy. How to restore the L1 blockade enhances the static CRC (mCRC) with proficient mismatch anti- tumor ability of suppressed T cells or improve the antitumor potency of T cells repair (pMMR) or microsatellite stable lethality of cytotoxic T cells has become the main focus in as predicted by a QSP model. (MSS) tumors, is one of the leading causes of immunotherapy. Bispecific antibodies, especially bispecific Journal for ImmunoTherapy cancer- associated deaths in USA.1 In recent T cell engagers (TCEs), have shown their unique ability of Cancer 2020;8:e001141. years, immune checkpoint inhibitors (ICIs) doi:10.1136/jitc-2020-001141 to enhance the patient’s immune response to tumors by stimulating T cell activation and cytokine production in have achieved a durable clinical response in Accepted 26 July 2020 an MHC- independent manner. Antibodies targeting the patients with melanoma, non-small- cell lung 2 checkpoint inhibitory molecules such as programmed cell cancer (NSCLC) and other cancer types. death protein 1 (PD-1), PD- ligand 1 (PD- L1) and cytotoxic However, the results of testing these drugs in lymphocyte activated antigen 4 are able to restore the mCRC patients with pMMR or MSS tumors cytotoxic effect of immune suppressed T cells and have also were disappointing.3 Novel therapeutic shown durable responses in patients with malignancies. agents or combination strategies are being However, both types have their own limitations in treating tested and accurate biomarker-guided patient certain cancers. Preclinical and clinical results have selection is needed to determine patients who emphasized the potential of combining these two antibodies 4 5 to improve tumor response and patients’ survival. However, will most likely benefit from the treatment. the selection and evaluation of combination partners Note that all abbreviations are described in clinically is a costly endeavor. In addition, despite advances online supplementary table S1. http://jitc.bmj.com/ made in immunotherapy, there are subsets of patients During the past few years, the US Food who are non- responders, and reliable biomarkers for and Drug Administration has approved different immunotherapies are urgently needed to improve the application of anti-programmed cell the ability to prospectively predict patients’ response and death protein (PD-1) inhibitors, including improve clinical study design. Therefore, mathematical and nivolumab (OPDIVO, Bristol-Myers Squibb) computational models are essential to optimize patient and pembrolizumab (KEYTRUDA, Merck) on September 26, 2021 by guest. Protected copyright. benefit, and guide combination approaches with lower cost and the anti-PD- ligand 1 (L1) inhibitor © Author(s) (or their and in a faster manner. atezolizumab (TECENTRIQ, Genentech). employer(s)) 2020. Re- use Method In this study, we continued to extend the permitted under CC BY. quantitative systems pharmacology (QSP) model we They have shown great potential for targeting Published by BMJ. developed for a bispecific TCE to explore efficacy of PD-1/PD- L1 interaction in the treatment 1Department of Biomedical combination therapy with an anti- PD- L1 monoclonal of patients with different types of cancer Engineering, Johns Hopkins University School of Medicine, antibody in patients with colorectal cancer. including melanoma, advanced NSCLC, Baltimore, Maryland, USA Results Patient-specific response toTCE monotherapy, renal cell carcinoma (RCC), head and neck 2Biotherapeutics Discovery anti-PD- L1 monotherapy and the combination therapy squamous cell cancer, triple-negative breast Research, Boehringer Ingelheim were predicted using this model according to each cancer and microsatellite instability-high Pharmaceuticals Inc, Ridgefield, patient’s individual characteristics. 2 6 mCRC (MSI- H mCRC). Typically, high Connecticut, USA Conclusions Individual biomarkers for TCE monotherapy, 3 PD-L1 expression in cancer cells is associated Department of Oncology and anti- PD- L1 monotherapy and their combination have with favorable prognosis and better disease- Sidney Kimmel Comprehensive been determined based on the QSP model. Best treatment Cancer Center, Johns Hopkins options for specific patients could be suggested based on free survival in response to PD-1/PD-L1 Medicine, Baltimore, Maryland, 7 8 their own characteristics to improve clinical trial efficiency. inhibitors. However, CRC cells express less USA The model can be further used to assess plausible PD- L1 and it has been reported by Valentini Correspondence to combination strategies for different TCEs and immune et al that the expression of PD- L1 in MSS Dr Huilin Ma; hma24@ jhmi. edu checkpoint inhibitors in different types of cancer. CRC is mainly restricted to tumor- infiltrating Ma H, et al. J Immunother Cancer 2020;8:e001141. doi:10.1136/jitc-2020-001141 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-001141 on 27 August 2020. Downloaded from immune cells.9 This could explain why MSS CRC patients and identified biomarkers for checkpoint inhibitor-based failed to respond to anti- PD-1/PD- L1 therapy. immunotherapy.30 Wang et al proposed a QSP model to Despite the recent failure of anti- PD-1/PD- L1 therapy determined potential predictive biomarkers to improve in MSS CRC patients, novel bispecific T cell engagers the antitumor response in HER2- negative breast cancer.31 (TCEs) have been developed and tested in treating CRC In this work, we have extended our QSP model to both in vitro and in vivo. Gonzalez- Exposito et al devel- include our previously developed TCE module and newly oped patient derived CRC organoids to explore the updated anti- PD- L1 module to study the efficacy of anti- mechanism of T cell bispecific antibody cibisatamab PD- L1 monotherapy and the combination with TCE (CEA- TCB) sensitivity.10 Bacac et al reported the anti- therapy for MSS CRC patients. We studied individual tumor activity of CEA- TCB in 110 cell lines and the mode biomarkers for the three therapeutic approaches—TCE of CEA- TCB mediated CRC cell lysis in a mouse tumor monotherapy, anti- PD- L1 monotherapy and their combi- model.11 Waaijer et al developed a T cell-engaging bispe- nation. In silico virtual clinical trials (VCTs) have been cific antibody (BsAb) to target cell surface A33 antigen conducted to compare the response to different treat- (huA33- BsAb), which is expressed in more than 95% of ments for the same cohort of virtual patients (VPs), human colon cancers.12 An ongoing phase I clinical trial and to discover predictive biomarkers. Our novel QSP of MGD007 ( Clinicaltrials. gov, NCT02248805), a gpA33 x model enables development of biomarker-guided patient CD3- BsAb, will provide more valuable information on the selection to improve clinical trial efficiency by providing clinical safety of this approach.13 the distributions of different biomarkers, recommend Even though there are over 500 publications listed rational therapeutic regimen and alleviate the rising in PubMed reporting the preclinical and clinical inves- demand for personalized treatment. tigations of BsAb,14 treating solid malignancies, which make up 90% of all cancers, remains extremely chal- lenging using BsAb because of their poor permeability.15 METHODS Although the clinical outcome of BsAb is more satisfac- Model structure tory in hematologic malignancies, some ongoing clinical The QSP model used in this study was based on our trials have shown promising outcomes in solid tumors.16 previous models developed for NSCLC and TCE.30 32 33 A phase I study (NCT02324257, NCT02650713) led by The model structure includes central (blood), peripheral Hoffmann- La Roche has shown the potential of CEA-TCB (other tissues and organs), tumor and tumor-draining (RO6958688; RG7802) monotherapy in treating patients lymph node compartments. The model is composed of with MSS mCRC, and 45% of the patients showed either several individual but interconnected modules such as partial response or stable disease. In a combination study cancer cell, T cell, immune checkpoint, antibody pharma- of CEA- TCB with atezolizumab, an anti- PD- L1 inhibitor, cokinetics (PK), antigen presentation and TCE modules 82% of the patients showed either partial response or (figure 1). The dynamics of major species in each stable disease, which was an exciting breakthrough for a module have been described in our previous publications http://jitc.bmj.com/ BsAb in a solid tumor.17 including tumor growth, antigen processing and presen- Although great achievements have been made by the tation, T cell activation and proliferation, T cell distribu- combination therapy of BsAb with anti-PD- L1 inhibitors tion, Treg dynamics, and TCE and immune checkpoint in solid tumors, possible disadvantages may arise such blockade PK and pharmacodynamics (PD). All governing as difficulties of determining the source of side effects, equations for the immune checkpoint and TCE modules drug–drug interactions,
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