Overview

Athenex is leading the development of NKT cells for cell therapy treatment of cancers.  We believe NKT cells are ideal cell types because of the intrinsic biology of NKT cells that may have unique advantages over T cell and NK cell-based technologies.  Early data we have generated are encouraging and suggest a promising platform for an allogeneic “off-the-shelf” approach. It is our aspiration to change cancer into a chronic disease by developing NKT cells to deliver long term durable responses that will improve the lives of cancer patients.

Science of NKT Cells

Current approved CAR-T treatments utilize autologous T cells harvested from patients, which require genetic manipulation, growth of cells in the laboratory and infusion back to the patient.  Allogeneic (off-the-shelf) T cell-based cell therapy is limited by the αβ T cell receptor (TCR) which will cause a very serious condition known as graft versus host disease (GvHD).  To avoid GvHD, conventional T cells require gene editing or some other modification of the TCR to enable off-the-shelf use.

NKT cells are a unique subset of lymphocytes that express NK cell surface markers as well as an invariant TCR. Like T cells, NKT cells recognize antigens presented by cell surface molecules.  In the case of NKT cells the cell surface presentation molecule is CD1d.  Unlike HLA molecules, which present antigens to conventional T cells, and which are highly variable person to person, CD1d has the same structure in all people.  Since the NKT cell TCR is invariant (the same in all people), NKT cells will not recognize other people’s tissues as foreign, and thus will not cause GvHD when used as an off-the-shelf therapeutic. Therefore, we believe NKT cells have the potential to be an ideal off-the-shelf platform for cancer immunotherapy.

NKT cells compare favorably to other cell types for several other reasons. NKT cells have been described to play an important role in bridging the innate immunity and adaptive immune systems.  They have the ability to activate and cross prime NK, T and B cells to propagate and amplify the immune response to tumors.

Even without a chimeric antigen receptor (CAR) or engineered TCR, NKT cells can selectively recognize and kill tumor-associated macrophages and myeloid derived suppressive cells to change the tumor microenvironment to be more immunogenic. Thus, when a CAR or engineered TCR is added to NKT cells, they have a dual killing mechanism.

Importantly, NKT cells are programed naturally to home to tissues, making them a potentially important tool in the treatment of solid tumors.  Lastly, NKT cells proliferate very well after activation and maintain immune memory due to persistence.

Addressing Unmet Medical Need

There are three main challenges with current CAR-T treatments that we believe need to be overcome to better serve cancer patients.

Access
  • Primarily used by transplant centers
  • Only 25% of eligible patients receive commercial CAR-T
Cost
  • Approximately $300,000+ for one dose of commercial CAR-T treatment
Efficacy and Safety
  • 60% of lymphoma patients do not have long-term, durable responses to commercial CAR-T cells
  • Cytokine release syndrome (CRS) rates of 30-40% with commercial CAR-T cells

Current treatments are autologous (meaning the starting cellular material comes from the patient), and community hospitals are not set up to manage the complex logistics for those products. By creating an allogeneic, off-the-shelf product that can be given in the outpatient setting, we would broaden access significantly with our NKT solutions.

Not only are current CAR-T therapies prohibitively expensive for patients, but they also cost academic hospitals even more to care for those patients because of prolonged intensive care unit (ICU) and hospital stays. Our goal is to leverage our ability to manufacture several hundred doses from a single healthy donor to create economies of scale, that will in turn reduce costs within the healthcare system and for payors. With our NKT cell therapies, patients would have access to an outpatient-based and well-tolerated treatment, which would lower the cost of caring for those patients.

Unfortunately, up to 60% of relapsed refractory lymphoma patients do not achieve long-term durable response from CAR-T treatment, and 30-40% of patients experience cytokine release syndrome (CRS). CRS is a serious side effect of CAR-T cells, often requiring intensive care unit (ICU) admission and which may cause death.  Neurotoxicity is another common complication of CAR-T cells.

Our CD19 CAR-NKT therapy has already shown an 80% overall response rate at the lowest doses. We believe there is the potential for use of higher doses and repeat dosing, which would help drive deeper and more durable responses. CAR-NKT cells have been well tolerated, with a CRS rate much lower than that of current CAR-T therapies. In addition, the incidence of neurotoxicity with CAR-NKT cells is much lower than that observed with CAR-T cells.

Our Pipeline

KUR-501 is an autologous (patient-derived starting material) GD2 CAR-NKT cell product being studied in pediatric neuroblastoma (GINAKIT2, NCT03294954). From this study, we have defined peripheral blood pharmacokinetics showing expansion of CAR-NKT cells in blood at all dose levels, persistence of CAR-NKT cells up to six months and have demonstrated tumor homing of CAR-NKT cells. We have also established safety and have good evidence of clinical activity in this challenging tumor.

KUR-502 is our allogeneic (off-the-shelf) CD19 CAR-NKT cell product currently in phase 1 (ANCHOR, NCT03774654) for relapsed/refractory lymphoma and leukemia. We are expanding ANCHOR to up to 12 clinical sites and will be enrolling patients at higher dose levels. Data we have reported so far show an overall response rate (ORR) of 80% and 60% complete response (CR) rate.

Our preclinical program, KUR-503, is an allogeneic (off-the-shelf) GPC3 CAR-NKT cell product. GPC3 is expressed by hepatocellular carcinoma (liver cancer), as well as other tumors, including gastrointestinal and pancreatic neoplasms.

In November 2021, Athenex announced an exclusive license agreement with the National Cancer Institute (NCI) to utilize TCRs targeting mutated p53, KRAS, and EGFR for the development of autologous and allogeneic cell therapies. Our plan is to expand the development of TCR based allogeneic NKT cell and autologous T cell therapeutic products for the treatment of human cancers. KRAS and p53 are the most commonly mutated genes in epithelial cancers, including lung and colorectal cancers. Combining TCRs with our allogeneic (off-the-shelf) NKT platform would allow repeat dosing, which would be important in driving responses in solid tumors.