Consolidation Therapy in Patients With Metastatic Solid Malignancies

Phase I/II Study of Low-Dose Cyclophosphamide, Tumor Associated Peptide Antigen (TAPA)-Pulsed Dendritic Cell (DC) Therapy and Low Dose GM-CSF, as Consolidation Therapy in Patients With Metastatic Solid Malignancies

This study evaluates the effectiveness of Tumor Associated Peptide Antigens (TAPA) pulsed dendritic cell injections as a potential consolidation therapy for patients with metastatic solid malignancies (SM). The investigators hypothesize that treatment of patients with metastatic SM who demonstrate a tumor response, or whose disease remains stable, after conventional first-line systemic therapy AND who lack an available, potentially curative therapeutic intervention and whose tumor cells and/or blood express at least one (1) TAPA of a defined panel of TAPAs will result in TAPA-specific T-cell responses without significant toxicities. The investigators also hypothesize CD4+ and CD8+ T-cell responses generated against specific TAPAs may translate into clinical antitumor activity.

Patients diagnosed with metastatic solid malignancies (SM), who have responded or whose disease remains stable following first line systemic therapy, and without available, potential curative therapeutic options, will be candidates for this Phase I/II study. Potentially eligible patients who agree to participate and sign a consent form will have their neoplastic cells and/or blood analyzed for the expression of a specific panel of Tumor Associated Peptide Antigens (TAPAs), including Sp17, ropporin, AKAP-4, PTTG1, Span-xb, Her-2/neu, HM1.24, NY-ESO-1 and MAGE-1. Patients whose tumors express one (1) or more of these TAPAs will receive three (3) days of subcutaneous Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) to increase bone marrow production of monocytes and dendritic cell (DC) precursors, and whole blood will be obtained by phlebotomy and/or leukapheresis for generation of autologous DCs. Patient's DCs will be generated in Kiromic's Cell Processing Good Manufacturing Process (GMP) facility, according to established Standard Operating Procedures, and activated by pulsing/loading them with the TAPA(s) relevant for each particular patient. Patients will receive five (5) days of low-dose cyclophosphamide prior to each vaccination with TAPA-pulsed DCs to decrease Treg activity. TAPA-pulsed DCs will be administered at a fixed dose of up to 1 X 107 DCs at least two (2) days following cyclophosphamide administration. DC vaccination schedule will be once every fourteen (14) days via subcutaneous (SC) and intradermal (ID) injections for a total of 6 vaccinations. Low dose GM-CSF will also be administered SC for five (5) consecutive days, starting three (3) to six (6) hours after each TAPA-pulsed DC treatment, to optimize immune responses. Patients will be followed on a weekly basis (or more frequently if required) to evaluate treatment-related toxicity. Immune responses and anti-tumor responses will be evaluated per protocol specifications. Continuation and stopping rules for the study will be defined based on toxicity/tolerability (Phase I) and/or immune responses (Phase II).

Inclusion Criteria:

1. Ability to provide informed consent.
2. Patients at least eighteen (18) years of age with histologically proven metastatic solid malignancies (SM) AND whose SM demonstrates a response, or whose disease remains stable, after conventional, first-line systemic therapy, AND who lack any available, potentially curative therapeutic intervention, will be eligible for participation in this study.
3. Expression of one (1) or more of the following TAPAs; Sp17, AKAP-4, Ropporin, PTTG-1, Span-xb, Her-2/neu, HM1.24, NY-ESO-1 and MAGE-1, by either reverse transcriptase polymerase chain reaction (RT-PCR) and/or immunocytochemistry, Western blotting or ELISA, in neoplastic cells and/or blood. For HER-2/neu expression, positive FISH results are acceptable. All lab tests will be performed in a CLIA certified facility
4. Presence of measurable or evaluable disease.
5. Patients must not have any active infectious process.
6. Patients must have a negative test for HIV, Hepatitis A, B, and C.
7. Patients must not be receiving active immunosuppressive therapy.
8. Patients must have discontinued systemic antineoplastic therapy (including endocrine and biological agents, as well as systemic corticosteroids) at least three (3) to four (4) weeks prior to enrollment. Toxicities from previous therapies must be grade 1 or less.
9. Patients may not have any known allergy to GM-CSF.
10. Patients must be willing to provide at least 250 mls of whole blood obtained by phlebotomy and/or consent to leukapheresis for DC generation.
11. Adequate renal and hepatic function (creatinine ≤ 2.0 mg/dl, bilirubin ≤ 2.0 mg/dl, aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 4X upper limit of normal range).
12. Adequate hematologic function (Platelets ≥ 60,000/mm3, lymphocytes ≥ 1,000 mm3, neutrophils ≥ 750/mm3, hemoglobin ≥ 10.0 g/dl).
13. Karnofsky performance status ≥ 70%.
14. Expected survival ≥ 6 months.
15. Patient Human Leucocyte Antigen (HLA) typing should demonstrate HLA-A*01, and/or HLA-A*02, and/or HLA-A*24 subtype restriction.
16. Either a female or male of reproductive capacity wishing to participate in this study must be using, or agree to use, one or more types of birth control during the entire study and for 3 months after completing the study. Birth control methods may include condoms, diaphragms, birth control pills, spermicidal gels or foams, anti-gonadotropin injections, intrauterine devices (IUD), surgical sterilization, or subcutaneous implants. Another choice is for a subject's sexual partner to use one of these birth control methods. Women of reproductive capacity will be required to undergo a urine pregnancy test before completion of the post-screening informed consent process.

Exclusion Criteria:

1. Patients without confirmed metastatic SM and/or response to conventional, first-line systemic therapy using standard RECIST criteria, or patients with confirmed metastatic SM and/or response to conventional, first-line systemic therapy using standard RECIST criteria, but who have an available, potentially curative therapeutic option will be excluded from participation in this study.
2. Patients without measurable or evaluable disease.
3. Patients receiving cytotoxic therapy (including endocrine and biological agents), radiation therapy, immunotherapy or non-topical steroids, within three (3) weeks of enrollment.
4. Active immunosuppressive therapy (excluding topical steroids) for any other condition.
5. Persistent fever (>24 hours) documented by repeated measurement or active, uncontrolled infection within 4 weeks of enrollment.
6. Active ischemic heart disease or history of myocardial infarction within six months.
7. Active autoimmune disease, including, but not limited to, Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), Ankylosing Spondylitis (AS), and Rheumatoid Arthritis (RA).
8. Pregnancy or breast feeding.
9. Active second invasive malignancy, other than basal cell carcinoma of the skin.
10. Life expectancy ≤ 6 months.
11. Patients with contraindications to CYP and/or GM-CSF.
12. History of allergy to CYP and/or GM-CSF.
13. Patients who have received organ transplants.
14. Patients with psychological or geographic conditions that prevent adequate follow-up or compliance with the study protocol.
15. Patients diagnosed with central nervous system (CNS) metastases or involvement at any time during disease course are excluded from the study.
16. Patient with HLA alleles not belonging to any of the following subtypes: HLA-A*01, or HLA-A*02, or HLA-A*24.