Protocol Number: 08-C-0155

Title:

Phase II Study of Metastatic Cancer that Overexpresses p53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-p53 TCR-Gene Engineered Lymphocytes and Dendritic Cell Vaccination

Number:

08-C-0155

Summary:

Background:

This study tests an experimental gene therapy cancer treatment that uses the patient's own lymphocytes (type of white blood cell), which are specially selected and genetically modified with a gene called anti-p53 T-cell receptor to target and destroy their tumor. Dendritic cells containing the p53 gene are also given as a vaccine.

Objectives:

To test the safety of the above treatment and determine if it can cause the patient's tumor to shrink.

Eligibility:

Patients 18 years of age and older whose cancer has spread beyond the original site and does not respond to standard treatment.

Patients with tissue type HLA-A*0201.

Patients whose cancer cells express the p53 gene.

Design:

Workup: Patients have scans, x-rays, laboratory tests, other tests as needed and leukapheresis, a procedure for collecting white cells to modify in the laboratory and later reinfuse into the patient.

Chemotherapy (days -7 to -1): Patients have chemotherapy for 1 week to prepare the immune system to receive the treated lymphocytes.

Cell infusion, vaccination and IL-2 treatment (day 0 for 1 to 5 days): Patients receive the anti-p53-T cell receptor containing lymphocytes by a 30-minute infusion through a vein. Starting within 24 hours of the cell infusion, they receive high-dose IL-2 infusions every 8 hours for a maximum 15 doses.

Vaccination (days 0, 7, 14 and 28): Patients receive p53-containing dendritic cells as a vaccine injected under the skin in the upper arm or thigh.

Recovery: Patients rest for 1 to 2 weeks to recover from the effects of treatment.

Tumor biopsy: Patients may undergo a biopsy (surgical removal of a small piece of tumor) after treatment to look at the effects of treatment on the immune cells in the tumor.

Follow-up: Patients return to the clinic 4 - 6 weeks after completing their regimen for a third set of vaccines and an evaluation. They then return for evaluations with a physical examination, review of side effects, laboratory tests and scans once a month for several months. They may have leukapheresis at some visits to allow researches to look at the effect of treatment on the immune system and check the viability of the infused cells. Patients whose tumor appears to be shrinking return every month for several more months. Those whose tumor is growing are referred to another study or back to their local physician. All patients return to NIH for a physical examination once a year for 5 years and then complete a follow-up questionnaire or telephone interview for another 10 years.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

a. Metastatic cancer that overexpresses p53 as assessed by immunohistochemistry. The criteria used to determine overexpression will be that used in the laboratory of Dr. Curt Harris. Ten fields will be evaluated at 40 times magnification and if greater than 5 percent of cells stain positive, the tumor will be categorized as an overexpressor.

b. Patients with melanoma or renal cell cancer must have previously received IL-2 and have been either non-responders (progressive disease) or have recurred. Patients with other histologies, not including hematologic malignancies, must have previously received first line and second line or higher systemic standard care (or effective salvage chemotherapy regimens) for metastatic disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred.

c. Greater than or equal to 18 years of age.

d. Willing to sign a durable power of attorney.

e. Able to understand and sign the Informed Consent Document.

f. Clinical performance status of ECOG 0 or 1.

g. Life expectancy of greater than three months.

h. Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen.

i. Must be HLA-A 0201 positive.

j. Serology:

a) Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system.

Patients who are HIV seropositive can have decreased immune - competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)

b) Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative.

k. Hematology:

a) Absolute neutrophil count greater than 1000/mm(3).

b) WBC (greater than 3000/mm(3)).

c) Platelet count greater than 100,000/mm(3).

d) Hemoglobin greater than 8.0 g/dl.

l. Chemistry

a) Serum ALT/AST less than or equal to 2.5 times the upper limit of normal.

b) Serum creatinine less than or equal to 1.6 mg/dl.

c) Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

m. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.

n. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients' toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).

o. Six weeks must have elapsed since prior MDX-010 therapy to allow antibody levels to decline, and patients who have previously received MDX-010 or Pfizer's anti-CTLA4 antibody, tremelimumab, must have a normal colonoscopy with normal colonic biopsies.

p. A biopsy must be available to evaluate p53 expression and the diagnosis should be confirmed by the Laboratory of Pathology, CCR, NCI.

EXCLUSION CRITERIA:

a. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

b. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.

c. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).

d. Concurrent systemic steroid therapy.

e. Systemic steroid therapy less than or equal to 4 weeks prior to study.

f. History of severe immediate hypersensitivity reaction to any of the agents used in this study.

g. History of coronary revascularization.

h. Documented LVEF of less than 45 percent in patients with:

-i. History of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, 2 degree or 3 degree heart block.

-ii. Age greater than or equal to 60 years old.

i. Documented FEV1 less than or equal to 60% predicted for patients with:

-i. A prolonged history of cigarette smoking (greater than 20 pack/year within the past 2 years).

-ii. Symptoms of respiratory dysfunction.

Special Instructions:

Currently Not Provided

Keywords:

Metastatic Cancer

Immunotherapy

Dendritic Cell Vaccine

Tumor Regression

Recruitment Keyword(s):

Metastatic Cancer

Melanoma

Kidney Cancer

Condition(s):

Skin Cancer

Melanoma

Kidney Cancer

Metastatic Cancer

Investigational Drug(s):

(Dendritic cells transduced with Advexin (Ad-p53)

(MSGV1AIB(anti-p53 TCR) PBL)

Investigational Device(s):

None

Intervention(s):

Drug: (Dendritic cells transduced with Advexin (Ad-p53)

Drug: (MSGV1AIB(anti-p53 TCR) PBL)

Drug: Aldesleukin

Gene Transfer: Anti-p53 TCR Transduced PBL

Gene Transfer: p53 Transduced Dendritic Cells

Supporting Site:

National Cancer Institute

Contact(s):

Recruitment Center - SB
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Building 10, Room 2-1730, Bethesda, Maryland 20892, United States
Phone: (866) 820-4505
Fax: (301) 451-1927
Electronic Address: ncisbirc@mail.nih.gov

Citation(s):

Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL, Miki T, Rosenberg SA. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3515-9.

Kawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JR, Appella E, Rosenberg SA. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med. 1994 Jul 1;180(1):347-52.

Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, Riddell SR. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995 Oct 19;333(16):1038-44.

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