Combination therapy of immunotoxin and checkpoint inhibitor
Inventors
Bigner, Darell • Chandramohan, Vidyalakshmi • Nair, Smita • Gromeier, Matthias • Bao, Xuhui • Pastan, Ira H.
Assignees
National Institutes of Health NIH • Duke University
Publication Number
US-11065332-B2
Publication Date
2021-07-20
Expiration Date
2036-11-04
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Abstract
Regional, tumor-targeted, cytotoxic therapy, such as D2C7-immunotoxin (D2C7-IT), not only specifically target and destroy tumor cells, but in the process initiate immune events that promote an in situ vaccine effect. The antitumor effects are amplified by immune checkpoint blockade which engenders a long-term systemic immune response that effectively eliminates all tumor cells.
Core Innovation
This invention relates to the combination therapy for treating tumors, specifically malignant gliomas, using a regimen comprising an immunotoxin and an immune checkpoint inhibitor. The immunotoxin includes a single chain variable region antibody fused to a PE38 truncated Pseudomonas exotoxin, with the antibody having CDR1, CDR2, and CDR3 regions as shown in specific sequences (SEQ ID NO: 6-11). The immunotoxin targets tumor cells expressing epidermal growth factor receptor (EGFR) and its variants such as EGFRvIII, enabling regional, tumor-targeted cytotoxic therapy.
The problem being addressed is the poor prognosis and survival outlook for patients with malignant gliomas such as glioblastoma, where median survival is less than 15 months despite current treatments. There is a need for advanced and efficient therapeutic approaches to improve patient survival. Additionally, gliomas have relatively low mutation rates, resulting in poor basal immunogenicity and limited response to immunotherapies, necessitating strategies that can enhance the antitumor immune response.
The invention solves this problem by utilizing immunotoxin therapy that not only directly kills tumor cells but also initiates immune events that stimulate a secondary antitumor immune response, acting as an in situ vaccine effect. When combined with immune checkpoint blockade targeting molecules such as PD-1 or CTLA-4, this combination amplifies the antitumor effects leading to a synergistic long-term systemic immune response that effectively eliminates tumor cells locally and in distant sites, including the immune-privileged central nervous system.
Claims Coverage
The patent includes two independent claims: one directed to a method of treating glioma tumors using a combination of a specific immunotoxin and an immune checkpoint inhibitor, and the other directed to a kit comprising these components. The main inventive features relate to the components used, their characteristics, and administration parameters.
Combination method for treating glioma tumors
Administering an immunotoxin comprising a single chain variable region antibody fused to a PE38 truncated Pseudomonas exotoxin with specific CDR regions (SEQ ID NO: 6-11) together with an inhibitor of an immune checkpoint selected from PD-1 and CTLA-4.
Kit for treating glioma tumors
A kit comprising the immunotoxin with the defined single chain variable region antibody fused to PE38 truncated Pseudomonas exotoxin (CDR regions as per SEQ ID NO: 6-11) and an immune checkpoint inhibitor targeting PD-1 or CTLA-4.
Immunotoxin characteristics
The immunotoxin may have the PE38 truncated Pseudomonas exotoxin fused to a KDEL peptide to enhance intracellular retention and cytotoxicity, and may have specific amino acid sequences (SEQ ID NO: 1 through SEQ ID NO: 5).
Administration timing and routes
The immune checkpoint inhibitor is administered within 30 to 7 days of the immunotoxin. The immunotoxin can be administered directly to the tumor, and the checkpoint inhibitor can be given via diverse routes consistent with known methods for such inhibitors.
The claims cover both the therapeutic method using a specific immunotoxin combined with particular immune checkpoint inhibitors to treat glioma tumors and a corresponding kit with these components. The invention emphasizes the defined molecular features of the immunotoxin and the particular immune checkpoints targeted, with administration timing to achieve synergistic antitumor effects.
Stated Advantages
The combination therapy amplifies antitumor effects producing a long-term systemic immune response that effectively eliminates tumor cells.
The immunotoxin monotherapy directly destroys tumor cells and induces a secondary antitumor immune response acting as an in situ vaccine effect.
Combination with immune checkpoint inhibitors significantly increases cure rates compared to immunotoxin monotherapy.
The regimen provides improved survival benefit and can induce a memory immune response protecting against tumor rechallenge including in immune-privileged sites such as the brain.
Localized immunotoxin therapy achieves systemic antitumor immunity, delaying growth of distant untreated tumors, and such effects are enhanced by immune checkpoint blockade.
Documented Applications
Treatment of glioblastoma and other tumors expressing epidermal growth factor receptors, including EGFR and its variants such as EGFRvIII.
Use in murine models of glioma to demonstrate in vivo efficacy of combination therapy comprising D2C7 immunotoxin and immune checkpoint inhibitors targeting PD-1 and CTLA-4.
Use in subcutaneous and intracranial tumor models to achieve tumor growth delay, cures, and long-lasting immune memory protecting against tumor rechallenges both subcutaneously and intracranially.
Use of kits comprising the immunotoxin and immune checkpoint inhibitors for therapeutic administration.
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