Incysus Therapeutics: advancing science that makes sense

Harnessing the potential of γδ T cells, Incysus Therapeutics has developed two immunotherapy programs that are ready to be launched into the clinic.

Go to the profile of Incysus Therapeutics
Oct 31, 2019
0
0

Download the full PDF

In January 2015, with snowstorm Juno battering New York City and the subway closed for the first time in 110 years, biotech investor William Ho trekked through the blizzard, twenty blocks north from his office in Manhattan to the Waldorf Astoria to meet Lawrence Lamb, then a transplant immunologist at the University of Alabama at Birmingham.

The pair discussed using a then little-known type of immune cell, the γ6 T cell, as an immunotherapy for cancer. Making their vision a reality today, the com­pany has received US Food and Drug Administration approval for two investigational new drug (IND) applications, and is about to launch its first clinical programs, with Ho as CEO and Lamb as CSO.

While there has been much excitement over chime­ric antigen receptor T cell immunotherapies, which have demonstrated remarkable responses in patients with haematological cancers, solid tumors present a far greater challenge. In blood cancers, tumor cells are part of the circulation, making them readily accessible to immunotherapeutic cells that also circulate. By con­trast, solid tumors are densely packed, heterogeneous in nature and entwined with healthy organ tissue. Two major challenges for cell-based cancer therapies are achieving a high enough effector-to-target cell ratio to produce a therapeutic effect and designing a therapy that can recognize substantial differences in tumor cells within a single mass.

A combination approach

Incysus’s approach is to combine standard chemo­therapies with γ6 T cell therapy. Chemotherapies are able to kill large numbers of tumor cells, but they also select for drug-resistant tumors that are difficult to eliminate and kill the very immune cells needed to target any residual cancer. The Incysus strategy is to genetically modify γ6 T cells to survive use in com­bination with high doses of chemotherapy. These combinations enable the chemotherapy to break down the tumor and allow the modified γ6 T cells to reach the high concentrations needed to kill off any remaining cancer cells (Fig. 1). 

Fig. 1 | Drug-resistant immunotherapy by Incysus. MDSC, myeloid-derived suppressor cells.

A crucial role for γ6 T cells is to distinguish between the safe nonself, such as a pregnancy, and the dan­gerous self, such as cancer. γ6 T cells bridge between the cells mediating innate immunity, such as natural killer (NK) cells, and cells of the adaptive immune system, such as the better-known α3 T cells. Similar to NK cells, γ6 T cells respond to upregulated stress ligands and kill in the same manner. Unlike NK cells, γ6 T cells recognize these antigens through both the natural killer group 2D (NKG2D) receptor and the γ6 T cell receptor, allowing for an overlap in targeting. 

Activated γ6 T cells can act as professional antigen-presenting cells, and thus can directly phagocytose target cells, process tumor-associated antigens and cross-present the antigens to other T cells. In addi­tion, γ6 T cells produce cytokines that elicit stronger memory immune responses.

As a cell-based immunotherapy, γ6 T cells have a key advantage: they can be given directly from donor to patient without generating graft-versus-host dis­ease, unlike α3 T cells, which require extensive gene editing to remove major histocompatibility complex and T cell receptor genes. This means that Incysus can potentially create an off-the-shelf therapy, rather than personalizing the cell therapy for each patient.

In the clinic

Incysus is about to launch two clinical programs. The first, ICS-100, is exploring the use of allogeneic γ6 T cells in patients with leukemia and lymphoma undergoing haploidentical stem cell transplanta­tion. This therapy is a path toward a cure, but leu­kemic relapse remains at 51% in the first year, while infections with viruses such as cytomegalovirus and Epstein–Barr virus contribute to increased morbid­ity and mortality. The ICS-100 program will provide a high dose of γ6 T cells early in the recovery period with the aim of not only reducing infections but also reducing the probability of relapse.

The second program, ICS-200, is based on autolo-gous γ6 T cells that have been genetically modified to express the MGMT gene, which confers resis­tance to alkylating chemotherapies. These Drug Resistant Immunotherapy (DRI) γ6 T cells remain alive and functional even when combined with the

chemotherapy. In this phase 1 trial, patients with newly diagnosed glioblastoma (GBM) will receive chemotherapy in combination with Incysus’s novel DRI. The chemotherapy drives DNA double-stranded breaks that trigger a DNA damage repair cascade, activating responses to fix or eliminate cells with DNA damage. This process increases immune sig­nals on cancer cells by up to 700% (even among chemoresistant cells), which γ6 T cells use as a cue to eradicate any residual cancer.

In animal GBM models, chemotherapy alone offers a median survival time of 60 days. In combination with Incysus’s DRI-modified γ6 T cells, 80% of animals survived until 150 days, after which the animals were sacrificed and their brains analyzed, revealing that the DRI combination eradicated the tumors. The same combination also increased median survival in ani­mals implanted with chemotherapy-resistant tumors by 41% (P = 0.017).

Incysus welcomes enquiries from patients and potential investors or collaborators to bring this novel therapeutic approach to the millions of patients with cancer whose lives could be transformed by a suc­cessful immunotherapy to treat solid tumor cancers.

­
Contact

William Ho, President and CEO
Incysus Therapeutics, Inc.
New York, NY, USA
Tel: +1-646-600-6438
Email: info@incysus.com 
Website: www.incysus.com 

Go to the profile of Incysus Therapeutics

Incysus Therapeutics

Incysus Therapeutics, Inc. ("Incysus") is a biotechnology company advancing a unique and innovative approach towards the treatment of cancers. We are focused on delivering a novel off-the-shelf product for the treatment of cancer. By using genetically modified gamma-delta (γδ) T cells, our technology addresses the challenges that immunotherapies face when targeting cold, low mutation cancers. Incysus received approval of an Investigational New Drug (IND) application by the U.S. Food and Drug Administration (FDA) to test the safety and activity of an allogeneic donor γδ T cell infusion for cancer immunotherapy in a Phase I trial. This is an initial step towards developing 'off-the-shelf' cell therapies with γδ T cells. Incysus has also received FDA approval of a second IND allowing for the initiation of a Phase I clinical trial of our novel Drug Resistant Immunotherapy (DRI) platform. This trial for the treatment of patients with newly-diagnosed glioblastoma (GBM) is the first genetically modified γδ T cell product candidate cleared to enter the clinic. Our unique DRI technology offers an elegant approach to immuno-oncology that deals with multiple mechanisms of tumor resistance and immunosuppression. We believe this approach will lead to the development of more effective treatments for patients with difficult-to-treat solid tumor cancers.

No comments yet.