Patient case: 45-year-old female with colon cancer; genetic feature: ERBB2 amplification

Clinical trial: Binary Oncolytic Adenovirus in Combination With HER2-Specific CAR VST, Advanced HER2 Positive Solid Tumors (VISTA)

Summary: This study involves patients with a type of cancer called HER2 (Human Epidermal Growth Factor Receptor 2) positive cancer. Because there is no standard treatment for this cancer at this time or because the currently used treatments do not work fully, this study asks patients to volunteer to take part in a research study investigating the safety and efficacy of using special immune cells called HER2 chimeric antigen receptor-modified Adenovirus-specific cytotoxic T lymphocytes (HER2-AdVST), in combination with intra-tumor injection of CAdVEC, an oncolytic adenovirus that is designed to help the immune system including HER2-AdVST react to the tumor.
  The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: oncolytic adenovirus (CAdVEC) and T cells (HER2-AdVST).
  CAdVEC is an oncolytic adenovirus that has been modified to include additional immune system stimulators. Specifically, genes that stimulate the immune system have been added to the oncolytic adenovirus. Oncolytic adenoviruses are viruses that are made to target and kill cancer cells without killing normal cells. Other oncolytic adenoviruses have been used in patients before however CAdVEC has not. In this study, CAdVEC will be injected into participants tumor at one tumor site which is most easiest to reach. Once the oncolytic adenovirus infects the cancer cells, the genes will be expressed, resulting in activation of the immune response so it can attack and kill cancer cells. However, because this approach may have limited effects on the other tumor sites that have not received the oncolytic virus injection, patients will also receive specific T cells following the intratumor CAdVEC injection. These T cells are special infection-fighting blood cells that can kill cells infected with viruses and tumor cells. Investigators have found from previous research that investigators can put a new gene into T cells and make them specifically recognize and kill cancer cells expressing HER2. In the past patients have signed a consent form that allowed us to put on their T cells the HER2 chimeric receptor with viral antigen receptor on their T cells. Investigators want to see if these cells can survive in a patients blood and affect the tumor. Although HER2 chimeric antigen receptor modified cytotoxic T lymphocytes have been used in patients before, HER2-AdVST has not.

Detailed description: Treatment with CAdVEC:
  On the first day of participants treatment, participants will receive an intratumor injection of CAdVEC.
  A blood sample will be obtained from participants on Day 1 of treatment before participants receive CAdVEC intra-tumor injection. Depending on the location of the participants tumor, different techniques can be used for intra-tumor injection. The most common route of injection is ultrasound-guided percutaneous (needle puncture in the skin) injection, but endoscopic (examination of the inside of the body by using a lighted, flexible instrument called an endoscope) ultrasound-guidance will be used for some patients as appropriate. Participants doctor will describe the procedures in more detail. Prior to percutaneous injection, participants may receive an anti-anxiety medicine such as diazepam (Valium) 5-10mg to calm participants down, to relieve muscle spasms, and provide sedation. If the participants tumor is injected during an endoscopic procedure, the procedure may be done under sedation.
  This study looks at different doses of CAdVEC. The decision about the dose participants receive is determined when enrolled on the study. The investigators and the study sponsor do not know which dose is the safest or which dose will work best.
  Treatment with HER2- AdVST:
  Earlier the participant gave blood for us to make Adenovirus-specific HER2 targeting cytotoxic T-lymphocytes (HER2-AdVSTs) in the lab. Invesitgators made the cells by first combining a special type of cells called dendritic cells (DCs) or monocytes with the T cells in the presence of produced mixtures of adenoviral proteins. Investigators then put a new gene in to those T cells to make them specifically attract to and kill HER2 positive tumors. As the T cells grow, investigators culture them by adding adenoviral proteins for stimulation and expansion. Investigators call those T cells: adenovirus-specific HER2- targeting T cells (HER2-AdVST). These cells will be grown and frozen for participants.
  Participants will receive HER2-AdVST cells infusion between day 3 and day 14 after receiving CAdVEC intra-tumor injections. Before receiving the T cell infusion, participants may be given Benadryl (diphenhydramine) and Tylenol (acetaminophen). Tylenol and Benadryl are given to prevent a possible allergic reaction to the T cell administration.
  This study looks at different doses of HER2-AdVST. The decision about the dose participants receive is determined when participants are enrolled on the study. The investigators and the study sponsor do not know which dose is the safest or which dose will work the best.
  Standard medical tests before treatment:
  Before being treated, participants will receive a series of standard medical tests:
  -  Physical exam and History
  -  Blood tests to measure blood cells, kidney and liver function.
  -  Pregnancy testing for female patients of childbearing potential (on blood or urine)
  -  Measurements of participants tumor by scans will be performed as standard of care procedures
  -  Color photography of skin lesions to estimate the size of the lesion, if present
  Standard Medical tests during and after treatment:
  Participants will receive standard medical tests during and after study treatment:
  -  Physical exams and History
  -  Blood tests to measure blood cells, kidney and liver function.
  -  Measurements of participants tumor by PET scans or CT scans 12 weeks after CAdVEC intra-tumor injection and then every 3 months up to 24 months per standard of care evaluation.
  -  Color photography of skin lesions to estimate the size of the lesion, if present.
  Study specific evaluations:
  Investigators will follow participants closely after treatment for any side effects for at least 2 years after the participants last infusion.
  To learn more about the way the T cells are working in the participants body, an extra 20-50 mL (4-10 teaspoons) of blood will be taken before CAdVEC injection, before the HER2-AdVST infusion, and at week 1, 2, 4 and 6 and 3, 6, 9 and 12 months after HER2- AdVST infusion. The blood may be drawn from participants central line at the time of the regular blood tests. Investigators will use this blood to see how long the T cells last and to look at the immune response to the participants cancer. Investigators may also ask participants to get a tumor tissue biopsy at week 12 if necessary.

Eligibility: Inclusion Criteria:
  1. Histologically confirmed HER2 positive solid tumors, including but not limited to: head and neck squamous cell carcinoma; cancer of the salivary glands; lung cancer; breast cancer; bladder cancer; gastric cancer; esophageal cancer; colorectal cancer; and pancreatic adenocarcinoma. HER2 positivity is defined as ≥2+ staining by IHC with the FDA-approved 4B5 antibody (Ventana), which refers to greater than weak-to-moderate staining intensity in >10% tumor cells.
  2. The disease must be deemed by the appropriate multidisciplinary tumor board unsuitable for curative surgery, radiotherapy, systemic therapy or any combination of the above modalities.
  3. Disease must have progressed after standard first line therapy, or without available effective treatment options.
  4. The patient must have at least one tumor site appropriate for intratumoral injection.
  5. The patient must have radiographically measurable disease as per RECIST 1.1.
  i.The patient must have adequate organ function within 7 days prior to consent for treatment as indicated by following measures:
  -  Hematologic: Absolute neutrophil count (ANC) ≥1.0 x 10^9/l; Hemoglobin ≥9 g/dl; Platelet count ≥ 100 x 10^9/l; PT or PTT ≤ 1.5 x ULN unless the subject is receiving anticoagulation.
  -  Hepatic function: bilirubin < 2 ULN, and AST and ALT < 3 ULN
  -  Renal Function: serum creatinine <2 x the ULN or creatinine clearance >30 mL/min.
  f.Prior HER2 targeted therapy is allowed if delivered at least 4 weeks prior to the enrollment.
  g.Prior immunotherapy is allowed if it was delivered at least 4 weeks prior to the enrollment.
  h.Eastern Cooperative Oncology Group (ECOG) performance status 2 or less. i.Females of childbearing potential must have a negative pregnancy test and agree to use contraception during on-study protocol therapy.
  j.Male subjects with pregnant partner/female partner of childbearing potential agree to use barrier contraceptive during the study to minimize the risk of embryo-fetal exposure.
  k.The patient is ≥ 18 years of age, and able to understand and give informed consent to study related procedures and treatments.
  Exclusion Criteria:
  1. Histologically confirmed HER2 positive solid tumors, including but not limited to: head and neck squamous cell carcinoma; cancer of the salivary glands; lung cancer; breast cancer; bladder cancer; gastric cancer; esophageal cancer; colorectal cancer; and pancreatic adenocarcinoma. HER2 positivity is defined as ≥2+ staining by IHC with the FDA-approved 4B5 antibody (Ventana), which refers to greater than weak-to-moderate staining intensity in >10% tumor cells.
  2. The disease must be deemed by the appropriate multidisciplinary tumor board unsuitable for curative surgery, radiotherapy, systemic therapy or any combination of the above modalities.
  3. Disease must have progressed after standard first line therapy, or without available effective treatment options.
  4. The patient must have at least one tumor site appropriate for intratumoral injection.
  5. The patient must have radiographically measurable disease as per RECIST 1.1.
  i.The patient must have adequate organ function within 7 days prior to consent for treatment as indicated by following measures:
  -  Hematologic: Absolute neutrophil count (ANC) ≥1.0 x 10^9/l; Hemoglobin ≥9 g/dl; Platelet count ≥ 100 x 10^9/l; PT or PTT ≤ 1.5 x ULN unless the subject is receiving anticoagulation.
  -  Hepatic function: bilirubin < 2 ULN, and AST and ALT < 3 ULN
  -  Renal Function: serum creatinine <2 x the ULN or creatinine clearance >30 mL/min.
  f.Prior HER2 targeted therapy is allowed if delivered at least 4 weeks prior to the enrollment.
  g.Prior immunotherapy is allowed if it was delivered at least 4 weeks prior to the enrollment.
  h.Eastern Cooperative Oncology Group (ECOG) performance status 2 or less. i.Females of childbearing potential must have a negative pregnancy test and agree to use contraception during on-study protocol therapy.
  j.Male subjects with pregnant partner/female partner of childbearing potential agree to use barrier contraceptive during the study to minimize the risk of embryo-fetal exposure.
  k.The patient is ≥ 18 years of age, and able to understand and give informed consent to study related procedures and treatments.

Relevance to patient case: possibly relevant