RESEARCH & DEVELOPMENT

Technology

VAXIMM’s technology is based on first-in-class oral T-cell activators that can be readily adapted to target a wide range of cancer-related antigens.

The platform is based on the live attenuated bacterial vaccine strain Ty21, which has been administered to millions of people as a prophylactic vaccine to temporarily protect them from typhoid fever. This strain has been proven to be very safe and well tolerated. All immunotherapies resulting from this platform are taken orally by the patient.

After oral ingestion, the modified Ty21a bacteria, which contain the cDNA of the desired cancer target(s), pass the stomach and invade the patient’s Peyer’s patches located in the small intestine. Uptake of the bacteria in macrophages, the eating cells present in these lymphoid tissues, leads to strong expression of and subsequently to a specific cellular immune response towards the encoded cancer antigen(s). These so-called “killer” T-cells then destroy the respective antigen expressing tumor or tumor stroma cells.

The oral bacterial technology enables delivery to the most immunocompetent organ of the body, targeting the lymphatic tissue of the gut, and has been shown to generate robust T-cell responses against many different antigens in animals and humans in first clinical studies. The low therapeutic doses required for specific T-cell activation make this approach suitable for continuous dosing (prime and boost administrations), without raising anti-carrier immunity, and provide another safety margin for carrier-related toxicity. The platform is suitable for addressing multiple targets with one treatment and can be combined with additional immune therapies. Another major advantage of this approach is the high modularity (plug and play), the low cost and robustness of the production process, and the rapid development timelines taking products from concept to clinical stage.

Clinical Programs

VXM01

VXM01 is an oral T-cell immunotherapy that is designed to activate T-cells to attack the tumor vasculature and, in several tumor types, attack cancer cells directly. VXM01 carries the vascular endothelial growth factor receptor-2 (VEGFR2), which is highly overexpressed on the tumor vasculature and on certain cancer cells as the target gene. The active, T-cell-mediated destruction of tumor vasculature cells leads to an increased infiltration of various immune cells into tumor tissue (inflammation). In preclinical studies, a murine analog VXM01 vaccine showed broad anti-tumor activity in different tumor types. This activity was linked to a VEGFR2-specific T-cell response and was accompanied by the destruction of the tumor vasculature and increased immune cell infiltration.

A Phase I/II trial in advanced pancreatic cancer showed that VXM01 was well tolerated and led to the activation of VEGFR2-specific cytotoxic T-cells, which was associated with significantly improved patient survival. A clinical Phase IIa trial in metastatic colorectal cancer also has been completed, and a trial in this indication in combination with avelumab is planned.

A Phase I trial was designed to evaluate the safety and tolerability of VXM01, as well as clinical and immunogenic response, in patients with recurrent glioblastoma. Fourteen patients were treated with VXM01, including three who were also treated with the anti-PD-1 checkpoint inhibitor, nivolumab. Of the fourteen patients treated, one patient experienced an objective response with VXM01 monotherapy and a durable response with the addition of nivolumab. During the observation period of up to 20 months, seven patients were still alive, all of them living for more than one year.

A Phase I/II trial evaluating VXM01 in combination with avelumab, a human anti-PD-L1 antibody, for the treatment of glioblastoma has been completed. The trial is part of a collaboration agreement with Merck KGaA, Darmstadt, Germany and Pfizer Inc.

VXM01 has received orphan designation from the European Commission and from the US Food and Drug Administration (FDA) for the treatment of glioblastoma.

Preclinical Programs

VXM04

VXM04 carries human mesothelin as the target antigen. Mesothelin is a protein that is overexpressed in several solid tumors, including mesothelioma, ovarian cancer and pancreatic adenocarcinoma. In preclinical studies, VXM04 has shown potent T-cell activation against mesothelin and stand-alone therapeutic activity in models of pancreatic cancer.

VXM06

VXM06 carries a modified Wilms Tumor Protein (WT1) as the target antigen. WT1 is overexpressed in several hematological malignancies and solid tumors, including acute leukemias, glioblastoma, colon cancer, pancreatic adenocarcinoma, and ovarian cancer. In preclinical studies, VXM06 has shown potent T-cell activation against WT1 and stand-alone therapeutic activity in models of leukemia. The safety profile of VXM06 has been demonstrated in a 3-month toxicity study in animals.

VXM08

VXM08 targets CEA, a human tumor-associated antigen overexpressed in many solid tumors, including colorectal cancer, lung cancer, gastric cancer, and pancreatic cancer. In preclinical studies, VXM08 has shown potent T-cell activation against its target antigen as well as stand-alone therapeutic activity in models of colorectal and lung cancer.

VXM10

VXM10 targets PD-L1, an immunomodulatory antigen upregulated in many solid tumors as well as hematological malignancies. VXM10 is currently in preclinical development and has shown stand-alone therapeutic activity in models of leukemia.

Publications

Oral DNA vaccination targeting VEGFR-2 combined with anti-PD-L1 avelumab in patients with progressive glioblastoma, a phase I/II study

Wolfgang Wick et al., ASCO Annual Meeting 2019

Modulating T cell immunity in tumors by targeting tumor-associated antigens, PD-L1 and neoantigens using a versatile live attenuated oral Salmonella DNA vaccination platform

Sébastien Wieckowski et al., AACR Annual Meeting 2018

VXM01 phase I study in patients with progressive glioblastoma – Final results

Wolfgang Wick et al., 2018 ASCO Annual Meeting

Fast and cost-effective oral delivery technology of personalized T-cell vaccines based on a live attenuated bacteria platform

Heinz Lubenau et al., European Neoantigen Summit 2018

A versatile live attenuated oral Salmonella DNA vaccination platform for modulating T cell immunity against tumor neoantigens

Heinz Lubenau, European Neoantigen Summit 2018

A phase 1 trial extension to assess immunologic efficacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer

Schmitz-Winnenthal, F.H. et al., OncoImmunology 2017: e1303584

Live attenuated oral Salmonella platform for effective targeting of PD-L1 and multiple tumor-associated epitopes

Heinz Lubenau et al., AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2017

A live attenuated Salmonella Typhimurium oral T cell vaccine against PD-L1 protects 100% of animals from a leukemia challenge

Heinz Lubenau et al., Third Cri-CIMT-EATI-AACR International Cancer Immunotherapy Conference 2017

Non-clinical safety, immunogenicity and anticancer efficacy of VXM06, a live attenuated Salmonella Typhimurium oral T cell vaccine against WT1

Sébastien Wieckowski et al., Third Cri-CIMT-EATI-AACR International Cancer Immunotherapy Conference 2017

VXM01 phase I study in patients with operable progression of a glioblastoma to examine safety, tolerability, immune and biomarker response to the VEGFR-2 DNA vaccine VXM01

Wolfgang Wick et al., ASCO Annual Meeting 2017

Non-clinical safety, immunogenicity and antitumor efficacy of live attentuated Salmonella Typhimurium-based oral T-cell vaccines VXM01m, VXM04m and VXM06m

Sébastien Wieckowski, PhD, et al., AACR Annual Meeting 2017

Non-clinical safety and antitumor efficacy of live attentuated Salmonella typhimurium-based oral T-cell vaccines VXM01m, VXM04m and VXM06m

Sébastien Wieckowski, PhD, et al., EORTC-NCI-AACR Symposium 2016

A phase 1 trial extension to assess immunologic efficacy and safety of prime – boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer

Schmitz-Winnenthal, F.H. et al., ASCO Annual Meeting 2016

Preclinical studies related to a phase 1/2a TRIAL to investigate the immunologic impact, anti-tumor efficacy and safety of VXM01, an oral T-cell inducing vaccine, in late stage colorectal cancer patients

Podola, L. et al., CIMT Annual Meeting 2016

Anti-angiogenic activity of VXM01, an oral T-cell vaccine against VEGF receptor 2, in patients with advanced pancreatic cancer: A randomized, placebo-controlled, phase 1 trial

Schmitz-Winnenthal, F.H. et al., OncoImmunology 2015, 4 (4): e1001217

VXM01, an oral T-cell vaccine targeting the tumor vasculature:
Results from a double blind, randomized, controlled, first-in-man study in pancreatic cancer patients

Schmitz-Winnenthal, F.H. et al., ASCO Annual Meeting 2013

Double-blind, placebo-controlled first in human study to investigate an oral vaccine aimed to elicit an immune reaction against the VEGF-Receptor 2 in patients with stage IV and locally advanced pancreatic cancer

Niethammer, A. G. et al., BMC Cancer 2012, 12: 361

A DNA vaccine against vascular endothelial growth factor receptor 2 prevents effective angiogenesis and inhibits tumor growth

Niethammer A.G. et al., Nature Medicine 2002, 8(12):1369-755