Abstract 5991
Background
The E3 ubiquitin ligase Cbl-b is a key master immune checkpoint regulator that limits immune activation critical for anti-tumor immunity. We first reported that Cbl-b deficiency in mice confers spontaneous in vivo rejection of tumor cells. This checkpoint role in anti-tumor immunity was confirmed in multiple mouse and human studies. Further discovery efforts led to the advancement of APN401, an ex vivo human Cbl-b siRNA-based autologous cellular therapy, currently in clinical development in patients with advanced solid tumors. APN401 has been target validated and its preclinical efficacy was established in various mouse syngeneic tumor models. We present here the potent anti-tumor efficacy of APN401 immunotherapy of Cbl-b silenced murine T cells in a syngeneic MC38 colorectal tumor model.
Methods
T cells isolated from MC38 tumor-bearing donor C57Bl/6 mice were silenced ex vivo with APN401 murine Cbl-b specific siRNA vs control siRNA, adoptively transferred into MC38 tumor-bearing recipient mice, and tumor growth was monitored using an in vivo imaging system.
Results
Murine APN401 treatment resulted in a significant MC38 tumor growth inhibition of 63% (p = 0.008) vs controls after just a single dose application. Profound anti-tumor efficacy induced by Cbl-b-silenced T cells strongly correlated with enhanced production of TH1 cytokines IL-2 and IFN-γ. Furthermore, in vivo tracking of fluorescently labeled and silenced T cells revealed migration to relevant lymphoid organs and local tumor sites. Murine APN401 treatment was safe and well-tolerated similar to recent human APN401 clinical phase Ia study results in patients with advanced solid tumors.
Conclusions
In a model of murine colon cancer, Cbl-b-silencing induced vigorous in vivo anti-tumorigenic immune responses. The treatment modality was safe and well tolerated. These data provide direct preclinical proof of concept that siRNA-based silencing of Cbl-b provides a novel, effective and tunable approach as cellular immunotherapy. Targeting Cbl-b through human APN401 cell therapy is a promising novel therapeutic approach for the treatment of solid cancers, also highlighted by our fast-tracked global APN401 clinical development.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
4021 - Prospective pathological experience with research biopsies in the context of clinical trials at Vall d’Hebron Institute of Oncology
Presenter: Paolo Nuciforo
Session: Poster Display session 3
Resources:
Abstract
5603 - Development of a comprehensive next-generation targeted sequencing assay for detection of gene-fusions in solid tumors
Presenter: Vinay Mittal
Session: Poster Display session 3
Resources:
Abstract
4952 - Next-generation sequencing for better treatment strategy of cancer of unknown primary (CUP)
Presenter: Kang Kook Lee
Session: Poster Display session 3
Resources:
Abstract
4590 - Circulating-free DNA analysis from long-term surviving metastatic colorectal cancer patients undergoing surgery for resectable disease.
Presenter: Michele Ghidini
Session: Poster Display session 3
Resources:
Abstract
3696 - Ultra-sensitive detection of circulating tumor DNA identifies patients in high risk of recurrence in early stages melanoma
Presenter: Filip Janku
Session: Poster Display session 3
Resources:
Abstract
4295 - Identification of the founder BRCA1 mutation c.4117G>T (p.Glu1373*) recurring in Abruzzo and Lazio regions of Central Italy and predisposing to breast/ovarian and BRCA1-related cancers
Presenter: Daniela Di Giacomo
Session: Poster Display session 3
Resources:
Abstract
2214 - Enzalutamide (ENZA) and Apalutamide (APA) In vitro chemical reactivity studies and Activity in a Mouse Drug Allergy Model (MDAM)
Presenter: Mausumee Guha
Session: Poster Display session 3
Resources:
Abstract
5044 - Influence of genetic variation in COMT on cisplatin-induced nephrotoxicity in cancer patients.
Presenter: Bram Agema
Session: Poster Display session 3
Resources:
Abstract
3293 - Cardioprotective and anti-inflammatory effects of Empagliflozin during treatment with Doxorubicin: a cellular and preclinical study
Presenter: Vincenzo Quagliariello
Session: Poster Display session 3
Resources:
Abstract
3324 - Breast Cancer Organoids Model Treatment Response of HER2 Targeted Therapy in HER2-mutant Breast Cancer
Presenter: Xuelu Li
Session: Poster Display session 3
Resources:
Abstract