Geneos leverages DNA immunotherapy technology to identify, design, manufacture, and deliver tumor specific neoantigen-targeted (TSNA-targeted) personalized immunotherapies.
Geneos is developing personalized immunotherapies against tumor specific neoantigens which arise from gene mutations in cancerous cells. These mutations form during the development and progression of cancer. Data has shown that the immune system can recognize these mutated proteins as being different, “foreign”, from normal proteins and produce a neoantigen-targeted immune response. Furthermore, clinical studies with immune checkpoint inhibitors such as anti-PD1/PDL1 molecules (Keytruda®, Opdivo®, Tecentriq®, Imfinzi™, Bavencio®) have shown that these treatments appear to work better in tumors that have a higher mutational burden suggesting that neoantigen directed immune responses are important. Thus, the accumulating clinical evidence strongly points to the idea that developing tumor specific neoantigen-targeted immunotherapies is an attractive approach for treating cancer.

Geneos leverages DNA immunotherapy technology to identify, design, manufacture, and deliver tumor specific neoantigen-targeted (TSNA-targeted) personalized immunotherapies.

Geneos is developing personalized immunotherapies against tumor specific neoantigens which arise from gene mutations in cancerous cells. These mutations form during the development and progression of cancer. Data has shown that the immune system can recognize these mutated proteins as being different, “foreign”, from normal proteins and produce a neoantigen-targeted immune response. Furthermore, clinical studies with immune checkpoint inhibitors such as anti-PD1/PDL1 molecules (Keytruda®, Opdivo®, Tecentriq®, Imfinzi, Bavencio®) have shown that these treatments appear to work better in tumors that have a higher mutational burden suggesting that neoantigen directed immune responses are important. Thus, the accumulating clinical evidence strongly points to the idea that developing tumor specific neoantigen-targeted immunotherapies is an attractive approach for treating cancer.

Based in part on Inovio Pharmaceutical’s immunotherapy platform, Geneos’ neoantigen-targeting immunotherapy technology is designed to activate immune responses against cancer neoantigens. While other neoantigen-targeting approaches like peptides, RNA, and viral or bacterial vectors can also be used to produce neoantigens, the elegance of the Geneos Platform is that we are not creating or manufacturing immunogens that would then be placed into the body to induce a desired immune response. Instead, we create a fragment of DNA which encodes for the multiple targeted neoantigens and place that DNA into cells of the body (with the assistance of our proprietary electroporation system) allowing the body’s own cellular machinery to produce the desired neoantigens. This approach is designed to enable the body to create the neoantigen immunogens capable of inducing strong, multi-faceted immune responses to cancer similar to immune responses produced by the body to fight other viral or bacterial diseases.

Our patent protected and proprietary immunotherapy design, manufacturing, and treatment process is designed to:

Step 1
Step 2
Step 3
Step 4
Step 1: Tumor Genome Sequencing - Identify 1-1000+ Mutations

We start with a patient tumor sample (biopsy specimen) and then sequence the DNA from patient tumors.  We then identify 1-1000+ mutations by comparing the tumor genetic sequences to the patient’s normal genome.

Step 2: Neoepitope Identification - Identify and sort 1-100+ Potential Neoepitopes

After selecting appropriate mutated sequences to target for each patient, we make the synthetic neoantigen DNA sequences and insert these DNA sequences into a proprietary DNA plasmid. Multiple neoantigen DNA sequences can be inserted into a single plasmid and multiple DNA plasmids can be combined into a patient specific formulation enabling Geneos to deliver upwards of 1 – 100+ neoantigens simultaneously.

Step 3: Potent Vaccine Manufacturing - Vaccine Encoding the Selected Neoepitopes

We manufacture the patient specific neoantigen-coding DNA plasmids under cGMP conditions using a proprietary manufacturing process. Our manufacturing process can turn around neoantigen sequence to neoantigen product within 2 weeks.

Step 4: Immunotherapy Treatments Strategy - Target Disease, Patient Status, Dose, Regimen

The patient specific formulation is then injected into the patient by a proprietary in vivo electroporation (EP) based delivery system. Geneos has secured a license to the CELLECTRA® EP ‡ delivery technology from Inovio in the field of personalized therapies for cancer.

Then what?

A Healthcare Professional will inject the immunotherapy into the patient. Once the DNA plasmid gets into cells in the body, the cellular machinery that is normally used to produce useful proteins for the body’s functioning instead produces our targeted neoantigens using the genetic blueprint we provided in the DNA plasmid. These tumor specific neoantigens are then presented to the immune system, which activates the production of killer T cells specific to the targeted cancer.

Our approach has many advantages:

  • We can create neoantigen targeting immunotherapies
    against a wide array of cancer types.
  • Our immunotherapies activate, in vivo, strong T-cell responses
    (both CD4+ and CD8+ T-cells directed at the selected neoantigens).
    These T-cells are vital to fighting cancerous cells.
  • Our immunotherapies can be designed in days instead
    of months or years.
  • Our immunotherapies are manufactured by a fast and efficient process
    in the timeframe of days instead of months or years.
  • We can target upwards of 1 – 100+ neoantigens in the same patient
    specific formulation.
  • Proven approach –  120+ published manuscripts detailing
    the creation of multi-antigenic constructs for cancer and infectious
    disease targets using the optimized DNA-electroporation platform.
  • Our DNA sequence cannot replicate, cannot integrate into the
    genome, and is not able to cause disease.

  • Our immunotherapies do not need to be stored frozen.

What do the results look like?

GENEOS Platform based immunotherapies have, in phase I human studies for cervical dysplasia and HIV, generated best-in-class T-cell responses that are targeted, robust in magnitude, persistent, and functional.

In a phase II study, Inovio’s immunotherapy for cervical dysplasia demonstrated for the first time that a DNA-based immunotherapy can activate antigen-specific CD8+ T-cell responses with a killing effect on the targeted cells that leads to disease regression, thereby reversing disease progression to cervical cancer. Inovio has recently commenced a Phase III study for this program.

The results of a phase I/II head & neck cancer study of an immunotherapy for HPV-associated cancers were published in the journal Clinical Cancer Research in September 2018. This paper detailed the results of a patient with head and neck cancer treated with this immunotherapy who achieved a sustained complete response (full remission) on treatment with a subsequent PD-1 checkpoint inhibitor. In the overall study of 22 patients with and neck squamous cell carcinoma, Inovio reported 91% (20/22) of patients showed T cell activity in the blood or tissue (TILs). These positive results represent the first study and first report of T cell immune responses generated in cancer patients after treatment with the optimized DNA-electroporation based immunotherapy.

Importantly, human data to date has shown our approach has a positive safety profile without therapy related serious adverse events.

Geneos has extended the Inovio technology platform to deliver multiple neoantigen sequences simultaneously. In pre-clinical (mice and non-human primates) animal studies, Geneos has shown that multiple antigenic sequences delivered simultaneously can elicit strong CD8+ and CD4+ T cell responses against the target antigens.

 

Key publications

Neoantigens and Neoepitope Targeted
Preclinical Studies with the GENEOS Platform.

Synthetic DNA multi-neoantigen vaccine drives predominately MHC class I CD8+ T cell mediated effector immunity impacting tumor challenge.
Duperret EK, Perales-Puchalt A, Barlow J, Hiranjith GH, Chaudhuri A, Sardesai NY, Weiner DB, et al.  Cancer Immunol Res. 2018.

A Novel DNA Vaccine Platform Enhances Neo-antigen-like T Cell Responses against WT1 to Break Tolerance and Induce Anti-tumor Immunity.
Walters JN, Ferraro B, Sardesai NY, Weiner DB, et al. Mol Ther. 2017.

A human immune data-informed vaccine concept elicits strong and broad T-cell specificities associated with HIV-1 control in mice and macaques.
Mothe B, Hu X, Sardesai NY, Brander C, et al. J Transl Med. 2015.

Altered Response Hierarchy and Increased T-Cell Breadth upon HIV-1 Conserved Element DNA Vaccination in Macaques.
Kulkarni V, Valentin A, Sardesai NY, Gall SL, Mothe B, Felber BK, et al. PLoS One 2014.

Multivalent TB vaccines targeting the esx gene family generate potent and broad cell-mediated immune responses superior to BCG.
Villarreal DO, Walters JN, Laddy D, Yan J, Weiner DB. Hum Vaccin Immunother. 2014 Aug.

HIV-1 p24gag Derived Conserved Element DNA Vaccine Increases the Breadth of Immune Response in Mice.
Kulkarni V, Rosati M, Valentin A, Sardesai NY, Felber BK, et al. PLoS One. 2013.

 

Clinical Safety, Immunogenicity, and Efficacy Studies with the GENEOS Platform:

Immunotherapy targeting HPV 16/18 generates potent immune responses in HPV-Associated Head and Neck Cancer.
Aggarwal, C, Cohen RB, Morrow MP, Weiner DB, Bagarazzi ML, et al. Clin Cancer Res 2018.

Clinical and Immunological Biomarkers for Histologic Regression of High Grade Cervical Dysplasia and Clearance of HPV16 and HPV18 after Immunotherapy.
Morrow MP, Sardesai NY, Weiner DB, Trimble C, Bagarazzi ML, et al.  Clin Cancer Res 2017.

Augmentation of cellular and humoral immune responses to HPV16 and HPV18 E6 and E7 antigens by VGX-3100.
Morrow MP, Kraynyak K, Sardesai NY, Bagarazzi ML, et al.  Mol Therapy Oncolytics 2016. 

Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomized, double-blind, placebo-controlled phase 2b trial.
Trimble C, Morrow MP, Kraynyak K, Sardesai NY, Weiner DB, Bagarazzi ML, et al.  The Lancet 2015.

Immunotherapy against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses.
Bagarazzi ML, Weiner DB, Sardesai NY, et al.  Sci Transl Med. 2012. 

Synthetic Consensus HIV-1 DNA Induces Potent Cellular Immune Responses and Synthesis of Granzyme B, Perforin in HIV Infected Individuals.
Morrow MP, Tebas P, Sardesai NY, Weiner DB, Bagarazzi ML, et al.  Mol Therapy 2014.

Safety and comparative immunogenicity of an HIV-1 DNA vaccine in combination with plasmid interleukin 12 and impact of intramuscular electroporation for delivery.
Kalams SA, Parker SD, Sardesai NY, Weiner DB, et al.  J Infect Dis. 2013.

Tolerability of intramuscular and intradermal delivery by CELLECTRA® adaptive constant current electroporation device in healthy volunteers.
Diehl MC, Lee JC, Sardesai NY, Bagarazzi ML, et al.  Hum Vaccin Immunother. 2013.

 

Cancer Antigens and Immuno-oncology Combinations Targeted by the GENEOS Platform:


Synergy of immune checkpoint blockade with a novel synthetic consensus DNA vaccine targeting TERT.
Duperret EK, Wise MC, Weiner DB, et al. Molecular Therapy 2017.

Tapping the Potential of DNA Delivery with Electroporation for Cancer Immunotherapy.
Kraynyak KA, Bodles-Brakhop A, Bagarazzi M. Curr Top Microbiol Immunol. 2015.

Novel and enhanced anti-melanoma DNA vaccine targeting the tyrosinase protein inhibits myeloid-derived suppressor cells and tumor growth in a syngeneic prophylactic and therapeutic murine model.
Yan J, Tingey C, Sardesai NY, Weiner DB, et al. Cancer Gene Ther. 2014.

Highly optimized DNA vaccine targeting human telomerase reverse transcriptase stimulates potent antitumor immunity.
Yan J, Pankhong P, Sardesai NY, Weiner DB, et al. Cancer Immunol Res. 2013.

Co-delivery of PSA and PSMA DNA vaccines with electroporation induces potent immune responses.
Ferraro B, Cisper NJ, Sardesai NY, Weiner DB, et al.  Hum Vaccin. 2011.

 

Reviews on DNA Vaccines & Immunotherapies:

Human papillomavirus therapeutic vaccines: targeting viral antigens as immunotherapy for precancerous disease and cancer.
Morrow MP, Yan J, Sardesai NY.  Expert Rev Vaccines 2013.

Electroporation delivery of DNA vaccines: prospects for success.
Sardesai NY, Weiner DB.  Curr Opin Immunol. 2011.

DNA Drugs Come of Age.
Morrow MP, Weiner DB. Scientific American. 2010.

DNA vaccines: ready for prime time?
Kutzler MA, Weiner DB. Nat Rev Genet. 2015.

 

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