Patients diagnosed with progressive and/or refractory solid malignancies (SM), who have
failed conventional therapy, and have no available, potentially curative therapeutic options,
will be candidates for this Phase I/II study. Following confirmation of disease progression
and/or refractoriness, eligible patients who agree to participate and sign a consent form
will have their tumor cells/tissues 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 performed for generation of autologous DCs.
Patient's DCs will be generated in Kiromic's Cell Processing 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 efficacy 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 immune efficacy (Phase II).
Inclusion Criteria:
1. Ability to provide informed consent.
2. Patients at least eighteen (18) years of age with histologically proven, progressive
and/or refractory SM without available, potentially curative therapeutic options will
be eligible for participation.
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 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.
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 mL, and up to 500 mL, 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,
AST and 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. 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.
16. Patient Human Leucocyte Antigen (HLA) typing should demonstrate HLA-A1 restriction.
Exclusion Criteria:
1. Patients without confirmed progressive and/or refractory SM using standard RECIST
criteria, or those with confirmed progressive and/or refractory SM using standard
RECIST criteria, but who may have available, potentially curative therapeutic options
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) to four (4)
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 of less than 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 participation in this study.
16. Patients without HLA-A1 restriction.
