Science Overview

Guanylyl Cyclase C (GCC; GUCY2C)

Guanylyl Cyclase C, one of a family of seven homologous proteins, is selectively expressed by intestinal epithelial cells, where it catalyzes the production of cGMP following binding of its paracrine hormones guanylin or uroguanylin. Also, GUCY2C is normally expressed by neurons of the hypothalamus and striatum in brain.

Of importance, GUCY2C is over-expressed by nearly all metastatic colorectal cancers, and a substantial subset of metastatic gastric, esophageal, and pancreatic cancers.

Limited expression in normal tissues and universal overexpression by primary and metastatic colorectal tumors, and a subset of other GI tumors, makes GUCY2C a useful molecular biomarker to detect metastatic cancers, and a potential chemotherapeutic and immunotherapeutic target in patients with those cancers.

Cancer Vaccine (Immunotherapeutics)

Cancer vaccines include immunotherapeutics that treat cancer by administering cancer-specific antigens to stimulate the patient’s immune system.

Cancer vaccines can be classified into “preventative vaccines” and “therapeutic vaccines.” Although preventative vaccines have a large market share in the global cancer vaccine market, such market share is forecasted to decrease due to the emergence of therapeutic vaccines.

Therapeutic vaccines are immunotherapeutics that are less toxic compared to standard therapeutic modalities like radiation therapy and chemotherapy. By increasing the survival rate of cancer patients whose overall health is more tenuous, and thereby providing more treatment opportunities, therapeutic vaccines are expected to lead the growth of the cancer vaccine market.

 

The Cancer Vaccine Market

  • The global cancer vaccine market was USD 2.5 billion in 2015 with an annual average growth rate of 17%
    • Forecasted to reach USD 7.5 billion by 2022
  • Currently, there are three types of cancer vaccines available in the market:
    • GARDASIL by Merck Sharpe & Dohme
      • Preventative vaccine for cervical cancer
      • Recorded a blockbuster sale in 2015 and reached USD 860 million in Q3 of 2016 with a sharp increase of 38% compared to the same quarter of 2015
    • CERVARIX by GlaxoSmithKline
      • Preventative vaccine for cervical cancer
    • PROVENGE from Valeant
      • The first and only FDA-approved therapeutic vaccine for prostate cancer
      • Registered as the most expensive cancer treatment drug covered by Medicare in the U.S.

CAR-T Therapy

Gene therapy refers to genetic alteration of cells for preventative or therapeutic purposes. Cell-based cancer immunotherapy is the main type of cancer immunotherapy that encompasses gene therapy.

Among the cell-based cancer immunotherapies, CAR-T therapy isolates T-cells (immune cells) from a patient’s blood and, using viral vectors, genetically engineers those T-cells to produce CARs on their surface. The numbers of these engineered T-cells are greatly expanded outside the patient and then they are injected back into the patient to attack cancer cells.

CAR-T therapy has the potential to eradicate active metastatic disease in patients. To date, the best successes with CAR-T cells has been in the treatment of blood cancers.

 

CAR-T Therapeutics Market

  • The global cancer immunotherapeutic market was estimated to be USD 62.57 billion in 2016
    • Forecasted to grow at an average annual growth rate of 14.3% to reach USD 160.24 billion in 2023 (according to the Stratistics Market Research Consulting’s report published in early 2018)
  • The global CAR-T cell therapeutics market in 2017 was USD 72 million
    • Expected to grow into USD 8.3 billion market by 2028 after consistent growth at an average annual growth rate of 53.9%
  • The largest CAR-T cell therapeutics market in the world is North America
  • Asia-Pacific market is currently the third largest behind Europe
    • Forecasted to grow at the fastest rate (CAGR 62.5% between 2019~2028) and replace Europe as the second largest market after North America by 2028
  • In 2017, Novartis’s KYMRIAH received the world’s first FDA approval for CAR-T therapeutics
    • Approved for treatment of patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL), a pediatric blood cancer known to be difficult to treat
  • Followed by Gilead’s YESCARTA, which enabled the commercial release of CAR-T therapeutics in the market
    • Approved for treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma

GCC Cancer Vaccine

The GCC Cancer Vaccine that is being developed recognizes GCC on cancer cells and induces immune responses by activating CD8+T cells and B cells.

Further, the vaccine prevents and treats recurrence and metastasis of GCC-expressing tumors, including colorectal, gastric, pancreatic, and esophageal cancer, by destroying only metastatic cancer cells but not normal cells within the intestine.

 

Orphan drug designation: Can be granted for applications including metastatic colorectal, pancreatic, gastric, and esophageal cancers

GCC CAR-T Cells

Solid tumor-targeted CAR-T therapeutics: CAR-T cell technologies have been rapidly advancing, with leukemia as one main target. However, development of CAR-T cell therapeutics for solid tumors has lagged. One major reason is the lack of a target that is highly selective for solid tumors.

However, CAR-T cells being developed by Liminatus target GCC, which is a demonstrated cancer cell-selective target. For this reason, GCC CAR-T cells are anticipated to lead clinical trials as opposed to other solid tumor cancer CAR-T approaches.

 

Utilization of Third-Generation CAR-T Technology

CAR-T cells have evolved to include intracellular costimulatory domains that allow the engineered cells to replicate and persist. Thus, with engagement of their target, they create a large number of CAR-T cells that attack cancer cells and last for a long period of time.

In first-generation CARs, transmission of signals and stimulation of T cells was limited because CD3ζ was the only intracellular costimulatory domain included. As the technology evolved, CD28, 4-1BB, OX40, etc. signaling domains were added in second- (CD3ζ plus one other signaling domain) and third- (CD3ζ plus two other signaling domains) generation CARs to enhance their ability to recognize and kill cancer cells.

Third-generation CARs incorporate CD3ζ plus two other costimulatory domains supporting robust expansion of CAR-T cells. However, enhancement of the ability of CAR-T cells to recognize and kill cancer cells and persist and expand using third-generation constructs has been associated with increased side effects with respect to normal cells. Even commercialized products (CD18-targeted CAR-T cells) have been associated with side effects and mortality in patients.

In this regard, the development of GCC CAR-T cells by Liminatus is significant because the target (GCC) is a highly compartmentalized antigen in normal tissues which, in turn, reduces concerns of autoimmunity and normal tissue injury characteristic of other CAR technologies and products.