Biopharma

Colorectal cancer vaccine

What is Colorectal cancer?

What is Colorectal cancer?1

- Colon cancer is a malignant tumor in the colon and rectum. Colorectal cancer is a cancer that starts in the colon or the rectum. These cancers can also be named colon cancer or rectal cancer, depending on where they start. Colon cancer and rectal cancer are often grouped together because they have many features in common.

Treatment1, 2

Prediction of prognosis in colorectal cancer is vital for the choice of therapeutic options. Factors such as tumor size, histological type and subtype, presence of signet ring morphology and the degree of differentiation as well as the presence of lymphovascular invasion and lymph node involvement are well known factors that influence outcome.



Treatment will depend on several factors, including the size, location, and stage of the cancer, whether or not it is recurrent, and the current overall state of health of the patient. Treatment options include chemotherapy, radiotherapy, and surgery.

Stage Treatment
Stage I
  • Surgical removal of the tumor and lymph nodes is usually the only treatment needed.(surgical resection) Most people don’t need additional treatments.
Stage Ⅱ
  • Surgical resection is usually the only treatment needed. Radiation and chemotherapy for cancers likely to recur.
Stage Ⅲ
  • Surgical resection is the first treatment.
    Adjuvant chemotherapy with 5-FU and leucovorin
    Radiation therapy: if cancer was large enough to grow into adjacent tissues.
Stage Ⅳ
  • Segmental resection(palliative) Palliative chemotherapy and radiotherapy.

Chemotherapy and Survival Rates by stage 1
Stage Ⅰ Stage Ⅱ Stage Ⅲ Stage Ⅳ
Stage (chemotherapy) Cancer chemotherapy is not performed because the possibility of recurrence is low. Though controversial, should the risk of recurrence is high, you may be asked to take chemotherapy. Please make decision after fully discussing with your doctor. Secondary chemotherapy to lower recurrence rate is the standard treatment. Cancer Treatment is more effective than symptomatic treatment. because it improves life extension and quality of life.
Survival Rates by stage The 5-year relative survival rate for people with stage I colon cancer is about 92%. For people with stage IIA colon cancer, the 5-year relative survival rate is about 87%. For stage IIB cancer, the survival rate is about 63%. The 5-year relative survival rate for stage IIIA colon cancers is about 89%. For stage IIIB cancers the survival rate is about 69%, and for stage IIIC cancers the survival rate is about 53%. Colon cancers that have spread to other parts of the body are often harder to treat and tend to have a poorer outlook. Metastatic, or stage IV colon cancers, have a 5-year relative survival rate of about 11%.

Adverse effects treatment

Postoperative complications

  • Pulmonary complications
    Anastomotic Leakage
    Bleeding and inflammation Dysuria or Micturition disorder
    Change in Bowel Habits
    Proctodynia

Colorectal Canr Anticancer Drug Adverse effects

Common adverse effects are Aleukaemia, Thrombocytopenia, Alopecia, Rash, Nausea, Vomiting and Fatigue.

Types of anticancer drugs Adverse effects
5-FU Nausea, Vomiting, Stomatitis, Diarrhea, Anorexia, Dermatitis, Rash, Alopecia
Caffeicitabine Nausea, Vomiting, Stomatitis, Diarrhea, Anorexia, Dermatitis, Rash, Alopecia and Hand-Foot Syndrome
Oxaliplatin Nausea, Vomiting, Diarrhea, Acroparesthesia
Irinotecan Diarrhea, Nausea, Vomiting, Abdominal Pain, Alopecia
Cetuximab Nausea, Diarrhea, Anorexia, Fatigue, Mucositis, Rash, Hypomagnesemia
Bevacizumab Hypertension, Proteinuria, Hemorrhage, Perforation, Delayed wound healing

Adverse effects of Radiation Therapy

  • Pelvic pain, Changes in bowel habits, Dysuria, Proctodynia, Diarrhea, Alopecia

Recurrence rate of colorectal cancer3-5

  • Recurrence rates(RRs) range from approximately 10% for disease confined to mucosa(stage Ⅰ) to >60% for tumors metastatic to more than four nodes(stage Ⅲ)

metastasis rates of colorectal cancer6-8

  • The 5-year overall survival rate after metastasis resection (i.e. R0 resections) varies from 25% to 58% for patients with livermetastasesand 24–52% for patients with lung metastases

GCC Vaccine Research Background and Patent / Technology

In the early 1990's, Dr. Waldman first identified Guanylate Cyclase C (GCC), an enzyme shown to be highly accurate for predicting recurrence of colorectal cancer and detecting the spread like esophagus, stomach, pancreas, duodenum, small intestine and liver. In other words, he recognized the unique utility for GCC in managing patients with colorectal cancer as a biomarker and target of that disease. The vaccine, which targets GCC, instructs the immune system to spot metastatic tumor cells and destroy them. With this breakthrough vaccine, metastases outside the colon may be prevented.
Even if cancer cells that are associated with GCC spread to other organs, the body recognizes GCC as normal. So it does not induce immune responses (Normal cells do not attack cancer cells) and develop into cancer. More than 50% of patients with colorectal cancer will develop metastatic. Dr. Waldmann injected DNA-based GCC vaccine into animals and humans by binding and transforming the adenovirus vector, which does not attack the normal cells. Viral vector vaccines were generated containing guanylyl cyclase C (GCC), expressed in normal intestinal epithelium and in all primary and metastatic human colorectal cancer (CRC) specimens. Immunization elicited CD8+ T without destroy normal cells in the large intestine. Moreover, responses effectively prevented development of metastases and treated established CRC metastases. After 15 years of research, and numerous preclinical lab and animal studies to evaluate biological activity and safety. The trial will assess the vaccine’s efficacy in blocking metastatic disease and improving patient survival.

GCC Vaccine mechanism

What is GCC?9

  • The enzyme encoded by the human gene GUCY2C is used as GC-C, Guanylate Cyclase 2C, Gyanylyl Cyclase C, and Intestinal guanylate cyclase.
  • GCC is a receptor for guanylin, uroguanylin, and diarrheagenic bacterial enterotoxin, exclusively expressed in the apical membrane of enterocytes and provides intracellular cGMP.
  • It is isolated from the lumenal compartment of the intestinal mucosa and can not enter the systemic vascular compartment.
  • GCC acts on intestinal epithelial cells to maintain fluidity and electrolyte homeostasis. It can also be used as a marker to detect the presence of GCC expression in metastatic gastric cancer and lung cancer.

Correlation between Colorectal / rectal cancer (CRC) and GCC11,12

  • The intestinal epithelium is the most rapidly self-renewing tissue of the mammalian body with a turnover time of 4-5 days.

  • GUCY2C binds the endogenous ligands guanylin, catalyzing the conversion of GTP to cGMP, and is required to maintain intestinal homeostasis. Thus, signaling by GCC and its downstream effector, cyclic GMP (cGMP) has emerged as a principal regulator of proliferation in human colon cancer cells. In that context, differentiated enterocytes in villi exhibit higher guanylin expression and ligand-dependent cGMP accumulation compared to proliferating progenitor cells in crypts

  • Hormone deficiencies offer over-expression of GCC
  • Dysregulation of GCC, Reflecting loss of endogenous ligands, might contribute to tumorigenesis by potentiating hyperproliferation.

  • Together with the uniform over-expression of GCC in human tumors, and the standard of care in which hormone deficiencies are treated by replacement therapy, the role of GCC as a tumor suppressor underscores the potential of oral administration of GCC ligands for targeted prevention and therapy of colorectal cancer.

GCC Research History

1999 ~ Present Progressive
  • Completion and implementation of Clinical 2-phase protocol (planning of clinical Trials in 5 hospitals including Harvard)

    Data analysis of Phase 2 data analysis and presentation

    Determination of Phase Ⅲ clinical trials conduct

  • Demonstrate the safety of vaccine.

    Destroy GCC-expressing metastatic tumors and boost levels of immunity through vaccination.

    Demonstrate that the ability of GCC-specific CD4+ T cell tolerance to contribute vaccine-induced antitumor immunity in mice.

  • The study reported that vaccines prevent development of metastasis and extended the median survival of mice.

    These results suggested not only the utility of GCC-specific immunotherapy for colorectal mucosal tissues, but the potential for malignancies of other mucosae such as stomach, esophagus, and genital cancer.

  • The most commonly lost gene products in colorectal carcinogenesis include guanylin and uroguanylin, the endogenous ligands for guanylyl cyclase C (GCC, GUCY2C), the intestinal receptor for diarrheagenic bacterial enterotoxins. GCC is a protein whose expression normally is restricted to intestinal epithelial cells, but universally over-expressed by metastatic colorectal tumors.

  • The study reported that Guanylyl Cyclase C mRNA have predicted to more accurately detect recurrence and metastatic patients with colorectal cancer.

ref.
1. 2018 American Cancer Society, Inc.; 2. Cancers(Basel) 2011 Jun; 3(2): 2767–2810.; 3. Biomark Med. 2013 Feb;7(1):159-167.; 4. CA Cancer J. Clin. 2004;54(6):295–308.; 5. Lancet. 2010;375(9719):1030–1047.; 6. Cancer Epidemiology 39 (2015) 734–744.; 7. Clin. Epidemiol. 4 (2012) 283–301.; 8. Ann. Thorac. Surg. 84 (2007) 324–338.; 9. Cancer Epidemiol Biomakers Prev. 2014 Novermber : 23(11): 2328-2337.; 10. Future Oncol. 2009 May ; 5(4): 509-522.; 11. Clevers,H.(2013). The intestinal crypt, a prototype stem cell compartment. Cell 154,274-284.; 12. Expert Rev Clin Pharmacol. 2013 Sep; 6(5): 557–564.;13. Expert Rev Clin Pharmacol. 2013 September ; 6(5): 557-564
Paper
2008 JNCI
Guanylyl Cyclase C-induced Immunotherapeutic Response Opposing Tumor Metastases w/o Autoimmunity
2009 AACRJ
Lineage-specific T-cell Response to Cancer Mucosa Antigen Oppose Systemic Metastase w/o Mucosal Inflammatory Disease
2013 Cell Press
GUCY2C: at the intersection of obesity and cancer
2014 EJOI
Selective antigen-specific CD4+T-cell, but not CD8+T or B-cell, tolerance corrupts cancer immunotherapy
2015 TJU
A Phase I Study of Ad5-GUCU2C-PADRE in Stage I and Stage II Colorectal Cancer Patients
2016 AACR
Obesity-induced colorectal cancer is driven by caloric silence of the Guanyln-GUCY2C paracrine signaling asix
The GCC cancer vaccine under development in the Viral gene is the world 's first cancer prevention
vaccine derived from colorectal cancer using Colorectal cancer markers.
    Alpha Holdings is investing in R & D for colorectal cancer vaccines in collaboration with the Viral gene.