INVAC-1 : A DNA vaccine targeting cancer

A DNA vaccine targeting a specific cancer marker

Cancer cells produce an enzyme which is key to their unlimited proliferation, but is nearly never expressed in normal cells. This enzyme is the telomerase.

Our lead product, INVAC-1 is a human telomerase DNA-based anti-cancer vaccine. It aims at mobilizing the immune system against the human telomerase complex (named hTERT), which is overexpressed in 90% of human tumors, but is virtually absent from normal cells. The vaccine activates the CD8+ Cytotoxic T cells, also called killer T Cells, which are capable of killing cancer cells. It also turns on CD4+ T helper cells, which regulate the immune response and stimulate the cytotoxic T cells.

INVAC-1 has completed its Phase I trial in various advanced cancer indications, demonstrating satisfying safety and immune response. The Phase II trial in Chronic Lymphocytic Leukemia (CLL) began in Q4 2017.

Invectys uses electroporation to intradermally inject INVAC-1 into the patient, and a needle-free injection system is also being evaluated.
In addition to its development, Invectys is working on combining INVAC-1 and other anti-cancer therapies. INVAC-1 could significantly increase the efficiency of other anti-cancer products, particularly Immune Checkpoint Inhibitors.

Below is additional information on INVAC-1:

Phase I clinical information
Phase II clinical study design
INVAC-1 Mechanism of Action

INVAC-1 Phase I clinical information

The product INVAC-1 completed its Phase I trial in various cancers in Q2 2018 (last patient last visit). Below is a brief summary of the study design and results:

Study design
- 20 advanced cancer patients injected monthly with electroporation
  - 3 cohorts with 100, 400 and 800 µg doses of INVAC-1
    (n=3 per cohort)
  - Extension cohort 800 µg (n=11)
  - 3 cycles per protocol
- 6 additional patients injected with needle-free injection device
Objectives
- Toxicity, tolerance, safety and immune responses
- Efficiency and immune response duration
Safety
- Vaccine treatment was safe and well tolerated
- No Dose Limiting Toxicity observed
Efficacy
- 1-year survival reached for 65% of patients
- 60% of patients demonstrated stabilized disease
- Overall median survival of 15 months
- Overall PFS was 2,7 months

Preliminary results were presented at ASCO 2017 and ESMO 2018.

Phase II clinical study design

The Phase II trial for INVAC-1 started in August 2018 (first patient first visit) in CLL, at the MD Anderson Cancer Center in Houston, TX, USA. 84 patients are expected to be enrolled along this study.

The study is divided into two groups (42 patients each):

Group 1: « watch and wait »		Group 2: Ibrutinib-treated patients as 1st or 2nd line treatment
Uncompromised immune system Duration: 6 doses of INVAC-1 as single agent injected at 4 week intervals for 6 months with follow-up of 2 years		Expected synergy with Ibrutinib Duration: 6 doses of INVAC-1 as single agent injected at 4 week intervals for 6 months with follow-up of 2 years

Outcome measures:

#1: Efficacy of INVAC-1 on MRD eradication rate in bone marrow, in Group 1 and/or Group 2
#2 : Progression free survival – impact on emergence of secondary tumors

Early read-out results for Phase II are expected in Q4 2019, and first top-line data should be available by mid-2020.

INVAC-1 Mechanism of Action

1) Preparing a vehicle for the hTERT DNA

INVAC-1 contains the DNA to produce human telomerase. Since telomerase gives its properties to tumor cells, Invectys’ version is slightly modified to avoid any risks: its functional component is inactivated, and it is designed to be rapidly broken down by the cell machinery. This DNA is injected intradermally through small, circular DNA strands called plasmids (A).

2) Making immune cells produce telomerase

The plasmids are forced into an Antigen Presenting Cell (APC) (B). INVAC-1 then finds its way to the nucleus of the APC, where it remains in episomal form (it is not integrated in the chromosomes, but is still expressed by the cell). Thus, the APC will start producing Invectys’ modified telomerase.

3) Breaking down and expressing telomerase

Because this modified telomerase is designed to be degraded, the APC will break it down into small components (peptides). These peptides will then migrate to the surface of the cell, where they will be presented by protein structures known as MHC-I (C) and MHC-II (D). It is important to note that MHC-I (aka HLA-1) can be found on all human cells, while MHC-II (aka HLA-2) is only expressed by certain immune cells.

4) Activating specialized T-Cells

With these telomerase peptides at its surface, the APC will migrate to the lymph nodes, where it will meet several categories of T-Cells: CD4+ T-helper cells (Th) (E), which stimulate the growth and the potency of other immune cells, and CD8+ Cytotoxic T Lymphocytes (CTL) (F), which eliminate dangerous cells. In the case of INVAC-1, these will be tumor cells. The antigen carried by the MHC-I will activate the CTLs, while the same antigen carried by the MHC-II will activate the T-helpers.
Because the immune response is highly specific, each peptide will activate a different set of Th and CTL cells.

5) Enabling Cytotoxic T-Cells

Once activated, the T-helper cells will produce cytokines, chemical messengers that will trigger the activation, growth and killing activity of the CTLs.

6) Recognizing telomerase on tumor cells

Like regular cells, tumor cells express a variety of peptides on their surface, thanks to the MHC complexes. The telomerase (G) in a tumor cell will be degraded by the proteasome (H), and presented by the cell’s MHC-I (I).

Since the body now produces active CTLs, able to recognize telomerase peptides, the CTLs will be able to bind with the peptide-carrying MHCs.

7) Destroying the cancer cells

Once attached to the cancer cell, the CTL will secrete a number of proteins (J), which will trigger a series of phenomena, leading to the death of the tumor cell.