Local Modulation of Immune Receptors to Enhance the Response to Dendritic Cell Vaccination in Metastatic Melanoma

NCT01216436 | Terminated Phase 1

• 1 other identifier: Pro00019239
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

Our proposed study is designed to test the safety of a new vaccine against melanoma. The induction of immune activity against cancers such as melanoma is a promising approach to cancer treatment, but to date, only a few clinically significant immune responses have been seen following vaccine therapy. This is an important problem, since there are very limited treatment options for patients with metastatic melanoma (melanoma that has spread to lymph nodes and organs). Studies suggest that monoclonal antibodies (mAbs) that block inhibitory receptors on immune cells can enhance the immune responses against cancer, but the intravenous injection of such mAbs has caused severe side effects in animals and humans. In our laboratory, we have developed a method to deliver mAbs and other proteins that block such inhibitory receptors locally at the site where immune responses against melanoma proteins are stimulated by vaccination, enhancing anti-melanoma immunity while avoiding the side-effects associated with intravenous injection of these immune modulators. This is achieved by loading dendritic cells, a type of immune cell, with RNA that encodes the immune modulator. The RNA-loaded dendritic cells then make the immune modulatory proteins and release them locally. By mixing these dendritic cells with additional dendritic cells loaded with melanoma proteins, the immune modulators are released at the site where anti-melanoma immune cells are stimulated. In this phase I trial, subjects with metastatic melanoma will undergo the process of leukapheresis, in which white blood cells are removed from the body. Monocytes, a type of immune cell, will then be purified from the white blood cells and cultured under conditions that will change them into dendritic cells. Half of these dendritic cells are then loaded with melanoma antigen RNA, which will lead to the production of melanoma antigen proteins within the dendritic cells. The remaining half of the dendritic cells will be either untreated or loaded with RNA encoding immune modulators so that these dendritic cells will release immune modulators at the site of vaccination. These dendritic cells will be mixed with the melanoma antigen-loaded dendritic cells and injected as a vaccine into lymph nodes. Each subject will receive six weekly injections of their own dendritic cells. Safety and toxicity will be closely monitored. In addition, immune responses against melanoma, as well as clinical responses, will be assessed.

Conditions

Metastatic Melanoma

Keywords

melanoma; immunotherapy; dendritic cell; GITR-ligand; CTLA-4

Outcome Measures

Primary Outcomes (1)

• Number of Participants with Adverse Events as a Measure of Safety and Tolerability

  Safety and Tolerability will be assessed for all subjects during the vaccination period and then regularly during the post-vaccination period. All subjects will then be followed clinically as would be done any subject with melanoma for a total of 5 years.

  A minimum of 6 months

Secondary Outcomes (1)

• Cellular anti-melanoma immune responses will be assessed

  A minimum of 4 months

Study Arms (4)

Vaccine plus untransfected DC

EXPERIMENTAL

Subjects in all study arms will be vaccinated with mature autologous dendritic cells transfected with a combination of RNAs encoding melanoma tumor associated antigens MART, Tyrosinase, gp100, and MAGE-3. In this Study Arm (Study Arm A), each subject will be coinjected with additional mature autologous dendritic cells that are not transfected with RNA.

Biological: Vaccination with RNA-transfected mature autologous DC

Vaccine plus GITRL RNA DC

EXPERIMENTAL

Subjects in all study arms will be vaccinated with mature autologous dendritic cells transfected with a combination of RNAs encoding melanoma tumor associated antigens MART, Tyrosinase, gp100, and MAGE-3. In this Study Arm (Study Arm B), each subject will be coinjected with additional mature autologous dendritic cells transfected with RNA encoding the immune modulator GITR-L.

Biological: Vaccination with RNA-transfected mature autologous DC

Vaccine plus antiCTLA4 RNA DC

EXPERIMENTAL

Subjects in all study arms will be vaccinated with mature autologous dendritic cells transfected with a combination of RNAs encoding melanoma tumor associated antigens MART, Tyrosinase, gp100, and MAGE-3. In this Study Arm (Study Arm C), each subject will be coinjected with additional mature autologous dendritic cells transfected with RNA encoding immune modulator anti-CTLA4 mAb.

Biological: Vaccination with RNA-transfected mature autologous DC

Vaccine plus GITRL/ antiCTLA4 RNA DC

EXPERIMENTAL

Subjects in all study arms will be vaccinated with mature autologous dendritic cells transfected with a combination of RNAs encoding melanoma tumor associated antigens MART, Tyrosinase, gp100, and MAGE-3. In this Study Arm (Study Arm D), each subject will be coinjected with additional mature autologous dendritic cells transfected with RNA encoding both GITR-L and anti-CTLA4 mAb immune modulators.

Biological: Vaccination with RNA-transfected mature autologous DC

Interventions

Vaccination with RNA-transfected mature autologous DC BIOLOGICAL

Dendritic cells (DC) will be administered at a dose of 20 million cells by intranodal injection under ultrasound guidance. Each subject will receive a total of six vaccinations at one week intervals

Vaccine plus GITRL RNA DC; Vaccine plus GITRL/ antiCTLA4 RNA DC; Vaccine plus antiCTLA4 RNA DC; Vaccine plus untransfected DC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with confirmed metastatic melanoma
• Karnofsky performance status greater than or equal to 70%.
• Estimated life expectancy \> 6 months.
• Age \> 17 years.
• Adequate hematologic function with:
• WBC \>= 3000 mm3
• hemoglobin \>= 9 mg/dl
• platelets \>= 100,000/mm3
• Adequate renal and hepatic function with:
• serum creatinine \< 2.5 mg/dl
• bilirubin \< 2.0 mg/dl
• AST/SGOT \< 70 U/L
• ALT/SGPT \< 70 U/L
• Alkaline Phosphatase ≤ 135 U/L
• Ability to understand and provide signed informed consent that fulfills Institutional Review Board guidelines.

You may not qualify if:

• Subjects undergoing concurrent chemotherapy, radiation therapy, or immunotherapy will be excluded.
• The subject has previously irradiated, surgically treated, or newly diagnosed central nervous system (CNS) metastases will be excluded (Pre-enrollment head CT is not required if not indicated by clinical signs or symptoms).
• Subjects with a history of autoimmune disease such as, but not restricted to, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, or multiple sclerosis will be excluded.
• Subjects with serious concurrent chronic or acute illness such as pulmonary (asthma or COPD), cardiac (NYHA class III or IV) or hepatic disease, or other illness considered by the principal investigator to constitute an unwarranted high risk for investigational drug administration will be excluded.
• Subjects with medical or psychological impediment to probable compliance with the protocol will be excluded.
• Subjects with concurrent second malignancy other than melanoma or non-melanoma skin cancer will be excluded. In the event of prior non-melanoma malignancies treated surgically, the subject must be considered NED (no evidence of disease) for a minimum of 3 years prior to enrollment.
• Subjects receiving steroid therapy (or other immunosuppressive agents such as azathioprine or cyclosporine A) are excluded on the basis of potential immune suppression.
• Subjects with inadequate peripheral vein access to undergo leukapheresis will be excluded.
• Female subjects with a positive pregnancy test, as well as those who have not previously undergone hysterectomy and/or bilateral oophorectomy and are unwilling to utilize a medically approved form of contraception, from the time of enrollment until 6 weeks after the final immunization, will be excluded.
• Male subjects, not previously surgically sterilized, who are unwilling to use a condom with spermicide during any sexual activity occurring over the entire immunization period and for the 6 weeks that immediately follow the final immunization will be excluded.
• Subjects with a documented history of severe allergic reaction to beta-lactams, eggs or soy products.

Sponsors & Collaborators

• Duke University: lead

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Publications (2)

• Pruitt SK, Boczkowski D, de Rosa N, Haley NR, Morse MA, Tyler DS, Dannull J, Nair S. Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. Eur J Immunol. 2011 Dec;41(12):3553-63. doi: 10.1002/eji.201141383. Epub 2011 Oct 26.

  PMID: 22028176 BACKGROUND

• Boczkowski D, Lee J, Pruitt S, Nair S. Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy. Cancer Gene Ther. 2009 Dec;16(12):900-11. doi: 10.1038/cgt.2009.39. Epub 2009 Jun 5.

  PMID: 19498460 BACKGROUND

MeSH Terms

Conditions

Melanoma; Diabetes Mellitus, Insulin-Dependent, 12

Interventions

Vaccination

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Immunotherapy, Active; Immunization; Immunotherapy; Immunomodulation; Biological Therapy; Therapeutics; Immunologic Techniques; Investigative Techniques; Primary Prevention; Preventive Health Services; Health Services; Health Care Facilities Workforce and Services; Communicable Disease Control; Public Health Practice; Public Health; Environment and Public Health

Study Officials

• Scott K Pruitt, MD, PhD

  Duke University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 1, 2010
• First Posted: October 7, 2010
• Study Start: January 1, 2010
• Primary Completion: October 1, 2013
• Study Completion: October 1, 2013
• Last Updated: May 25, 2015

Record last verified: 2014-04

Locations

US (1)