Geneos is focused on the development of Exquisitely Personalized Immunotherapies for Cancer based on our proprietary GT-EPICTM platform
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 and are different for each patient. Data has shown that the immune system can recognize these mutated proteins as being foreign, different 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®, ImfinziTM, 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 for their anti-tumor activity. 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 is focused on the development of Exquisitely Personalized Immunotherapies for Cancer based on our proprietary GT-EPICTM platform

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 and are different for each patient. Data has shown that the immune system can recognize these mutated proteins as being foreign, different 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®, ImfinziTM, 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 for their anti-tumor activity. 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 DNA Medicines technology, Geneos’ has developed the GT-EPICTM platform, designed to activate immune responses against cancer neoantigens. To do this, we create a fragment of DNA which encodes the multiple targeted neoantigens identified in each patient.  We then 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 inside the cells. The neoantigens thus produced naturally are then processed by the cells and presented to the immune system to induce a strong, multi-faceted immune responses to cancer similar to immune responses produced by the body to fight other viral or bacterial diseases.

Our proprietary GT-EPICTM platform integrates the multi-step personalized neoantigen identification immunotherapy design, manufacturing, and treatment process in an efficient manner:

Step 1
Step 2
Step 3
Step 4
Step 1: Tumor DNA and RNA Sequencing - Identify 1-1000+ Mutations

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

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

After selecting appropriate mutated sequences to target for each patient, we design, optimize and 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: Rapid cGMP Manufacturing - Vaccine Encoding the Selected Neoepitopes for each patient

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.

The integrated end-to-end Biopsy-to-Treatment turnaround time is currently at 6-8 weeks for each patient. We anticipate the timeline can be further shortened by further integration and automation of the manufacturing process chain. The rapid manufacturing timeline is a significant competitive advantage for Geneos.

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 6-8 weeks instead of over 12 weeks.
  • 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 constructs delivered by electroporation technology.
  • The optimized DNA electroporation technology has previously demonstrated a favorable safety profile in multiple human clinical studies enabling the translation to neoantigen targeted immunotherapies.
  • Our DNA sequence cannot replicate, cannot integrate into the genome, and is not able to cause disease.

  • Our immunotherapies demonstrate multi-year stability and do not need to be transported or stored frozen.

  • Our immunotherapies are highly patient specific and only require a small biopsy sample for the identification of the neoantigens and design of the treatment.  In particular, they do not require apheresis or large quantities of blood or other biological samples from the same patient. 

What do the results look like?

Geneos has deployed the GT-EPICTM platform to develop proof-of-concept pre-clinical data supporting the neoantigen targeting approach. Working in collaboration with Dr. David Weiner and his colleagues at The Wistar Institute, the team published in the prestigious journal Cancer Immunology Research (2019), feasibility studies demonstrating the techniques for rapidly screening neoantigens from multiple cancer tumor models and designing vaccine cassettes that allow for simple expression of dozens of antigens in a single formulation. This tumor specific approach resulted in a much higher CD8+ T-cell immunity than that achievable through other approaches. It also provided a simple, consistent and potent system that was effective at killing tumor cells, slowing tumor growth and profoundly delaying or preventing tumor progression in preclinical models of lung and ovarian cancer.

The team started by sequencing tumors from three different mouse models of lung and ovarian cancers and identifying the mutations that generate unique neo-epitopes, or bits of proteins that are altered or not present in the corresponding non-mutant molecule. They then designed DNA plasmids, each encoding a string of 12 of these epitopes, for a total of seven DNA vaccines and 84 neo-epitopes. These DNA vaccines were delivered in mice using controlled CELLECTRA® electroporation in order to enhance their potency. In contrast to prior approaches, in this study 75% of the epitopes driven by the vaccine were targeted by CD8+ T cells. This illustrates that platform limitations, synthetic DNA design and specifics of delivery can all impact the immune response outcome. Importantly, T cells isolated from the immunized mice and co-cultured with tumor cells only attacked and killed cells from their corresponding tumor type, demonstrating the high specificity of their cytotoxic activity. The researchers tested the vaccines in tumor bearing mice and observed a significant delay in tumor progression and a significant increase in survival after vaccination.

Based on the proof-of-concept pre-clinical immunology and tumor challenge data Geneos filed INDs and has now entered the clinic in three clinical programs using the GT-EPICTM platform to target brain tumors and advanced hepatocellular (liver) cancer in a patient specific manner.

Additional human clinical proof-of-concept for the Geneos approach comes from its development partner Inovio Pharmaceuticals and their clinical data based on their DNA Medicines programs. Inovio has demonstrated safety, and immunogenicity data in over 2000 patients across their infectious disease and cancer programs. More recently, Inovio reported remarkable PFS6 and OS12 data (ASCO 2020) in newly diagnosed GBM patients in their INO-5401 program utilizing 3 DNA encoded cancer antigens in combination with the cytokine immune-modulator IL12 DNA plasmid (INO-9012) and the PD1 inhibitor cemiplimab.

Geneos is has adopted a similar strategy combining its GT-EPICTM based personalized cancer vaccines with the DNA plasmid encoded cytokine IL12 (INO-9012, licensed from Inovio) with or without immune checkpoint molecules (PD1/PDL1).

Key publications by Geneos researchers

Neoantigens and Neoepitope Targeted
Preclinical Studies 

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 technology:

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 Geneos technology:


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.

 

‡ GENEOS, GT-EPICTM and the GENEOS logo are trademarks of Geneos Therapeutics, Inc.  All other trademarks are the property of their respective owners.