Reference Detail

Ref Type

Abstract

PMID

Authors

David R. Spigel; Eugene Ahn; Herbert L. Duvivier; Drew Rasco; Agnes Rethy; Chris Moore; Amy Yuet; Sandra Hankins; Swati Khanna; Joseph Dekker; Brian Van Tine

Title

Phase I study of MT-6402, a novel engineered toxin body (ETB) targeting PD-L1, in patients with PD-L1 expressing advanced solid tumors

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	82	12_Supplement	June 15 2022

URL

https://aacrjournals.org/cancerres/article/82/12_Supplement/CT152/702449

Abstract Text

This is the first-in-human study of MT-6402, a unique, first-in-class potent PD-L1-targeted engineered toxin body (ETB) capable of direct killing of PD-L1 expressing cells via rapid PD-L1-mediated internalization of a fused Shiga-like toxin A subunit (SLTA) resulting in permanent ribosomal inactivation. MT-6402 also delivers an HLA-A*02 restricted pp65 cytomegalovirus (CMV) antigen into PD-L1 expressing tumor cells leading to MHC-I presentation to existing CMV-specific cytotoxic T cells (antigen seeding). MT-6402 functions by targeting tumor and inhibitory immune cells directly and altering tumor immunophenotype to re-direct antiviral cytotoxic T cells into the tumor microenvironment. MT-6402 shows picomolar cytotoxic activity across several PD-L1 expressing cancer cell lines and treatment of human PBMCs results in selective depletion of PD-L1 positive cells. MT-6402 was well tolerated in non-human primates at doses above those which induce pharmacodynamic (PD) effect (reduction of CD14+ monocytes) in humans. This first-in-human study in patients with PD-L1-expressing advanced solid tumors will employ a modified toxicity probability interval design to determine MTD and will then enroll additional subjects at the MTD, to further explore safety and efficacy and determine RP2D. Results of the first dose cohort (16 micrograms/kg) are presented. Six patients received MT-6402. A significant and sustained reduction in CD14+ monocytes starting in cycle 2 was observed in patients on therapy beyond one cycle and was maintained with each MT-6402 administration, indicating HLA-independent PD effect consistent with preclinical observations. One HLA-A*02 and CMV+ patient with osseous metastases from NSCLC showed marked CMV-specific T-cell extravasation at day 8 and serum cytokine signatures consistent with antigen dependent responses and T cell mobilizations, suggesting engagement of MT-6402 antigen seeding. This patient has reduced intensity of metastatic bone lesions with 3/4 lesions resolving; the remaining lesion showing reduced uptake. Two patients had cytokine elevations at day 15, manifested by transient (1-12h), grade 2 infusion-related reactions and grade 2 cytokine release syndrome, which were subsequently prevented by steroid premedication. These results describe a novel approach to checkpoint modulation, leveraging direct PD-L1 cell kill and antigen seeding technology by the ETB. The results support further dose escalation and hold promise for development of MT-6402 for solid tumors, including in the R/R setting.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
MT-6402	MT-6402	2	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
MT-6402		MT 6402\|MT6402	PD-L1 Inhibitor 14	MT-6402 is an engineered toxin body that targets CD274 (PD-L1), potentially leading to killing of tumor cells expressing CD274 (PD-L1) and inhibition of tumor growth (Cancer Res 2022;82(12_Suppl):Abstract nr CT152).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CD274 positive	lung non-small cell carcinoma	predicted - sensitive	MT-6402	Case Reports/Case Series	Actionable	In a Phase I trial, MT-6402 treatment led to an antitumor immune response and decreased metastatic bone lesions in a CD274 (PD-L1)-positive non-small cell lung cancer patient with osseous metastases (Cancer Res 2022;82(12_Suppl):Abstract nr CT152).	detail...
CD274 positive	Advanced Solid Tumor	predicted - resistant	MT-6402	Preclinical - Cell culture	Actionable	In a preclinical study, MT-6402 treatment demonstrated cytotoxicity in a panel of CD274 (PD-L1)-positive cancer cell lines in culture (Cancer Res 2022;82(12_Suppl):Abstract nr CT152).	detail...