Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations.
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2019-05-29
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Abstract
Background
D2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma.Methods
To study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test.Results
D2C7-IT effectively killed CT-2A-dmEGFRvIII (IC50 = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC50 = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival (P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge.Conclusions
These data support the development of D2C7-IT and immune checkpoint blockade combinations for patients with malignant glioma.Type
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Chandramohan, Vidyalakshmi, Xuhui Bao, Xin Yu, Scott Parker, Charlotte McDowall, Yen-Rei Yu, Patrick Healy, Annick Desjardins, et al. (2019). Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations. Journal for immunotherapy of cancer, 7(1). p. 142. 10.1186/s40425-019-0614-0 Retrieved from https://hdl.handle.net/10161/25628.
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Scholars@Duke
Vidyalakshmi Chandramohan
The research work in my laboratory focuses on identifying novel immunotherapeutic targets for the treatment of brain tumors, specifically glioblastoma (GBM). My previous work includes the development of the dual-specific immunotoxin (IT) D2C7-IT, which is currently in Phase I clinical trials in recurrent GBM (rGBM) patients. My current research seeks to identify novel strategies to enhance the efficacy of D2C7-IT and other GBM-targeted cytotoxic therapies. In conjunction with this, my research includes the investigation of immune-related biomarkers to predict the clinical outcome of D2C7-IT therapy in patients with GBM.
Xuhui Bao
Cancer remains a significant global public health challenge and is the second leading cause of mortality in the United States. While traditional treatments such as surgery, chemotherapy, and radiotherapy have seen incremental advancements, the prognosis for many cancer patients continues to be poor. Over the past decade, the advent of novel targeted therapies, combination treatments, and immunotherapies has revolutionized the clinical approach to cancer care, offering new hope and changing treatment guidelines.
These innovative therapies have been successful in significantly prolonging the lives of 10-30% of patients, marking a milestone in cancer treatment. However, the majority of cancer patients still do not benefit from these novel immunotherapies, highlighting a clear need for more effective treatment modalities. The urgency to improve patient outcomes has sparked intense research into the discovery of new antitumor targets, a deeper understanding of resistance mechanisms to current immunotherapies, and the intricate dynamics of the tumor microenvironment.
Looking forward, the focus is on developing precision oncology strategies that can address these challenges. This includes not only identifying novel therapeutic targets but also unraveling the complex interactions within the tumor microenvironment that contribute to therapeutic resistance. By doing so, we aim to expand the arsenal of effective treatments and pave the way for more personalized and successful cancer therapies in the future.
Yen-Rei Andrea Yu
Annick Desjardins
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