WT1 Analog Peptide Vaccine in Patients With Multiple Myeloma Following Autologous Stem Cell Transplantation
- Conditions
- Multiple Myeloma
- Interventions
- Registration Number
- NCT01827137
- Lead Sponsor
- Sellas Life Sciences Group
- Brief Summary
The purpose of this study is to see if the investigator can help the immune system to work against myeloma through the use/administration of a peptide vaccine (immunotherapy agent) directed against the Wilms Tumor 1 (WT1) protein called galinpepimut-S (or GPS, for brief). Because cancer is produced by the patient's own body, the immune system does not easily recognize and fight cancer cells. The immune system needs to be "trained" to do this; the latter goal is accomplished by using a vaccine consisting of selected fragments of the target antigen, in this case, WT1.
This disease has been selected for this study because the WT1 protein is often present in myeloma cells. WT1 is a gene that is involved in the normal development of kidneys and other organs. When the WT1 gene becomes abnormal, it can make proteins involved in the development of cancer, i.e., can acquire the properties of a true "oncogene". This study will determine whether the vaccine against the WT1 antigen (present in malignant plasmacytes) can cause an immune response which is safe, but also able to keep the myeloma from either coming back or progressing.
- Detailed Description
Key Features:
- This is a Phase 1/2 clinical study conducted in patients with newly diagnosed high-risk multiple myeloma to examine the effects of GPS immunotherapy on clinical and immunobiological indices. The study is titled "A Pilot Trial of a WT1 Analog Peptide Vaccine (Galinpepimut-S) in Patients With Multiple Myeloma Following Autologous Stem Cell Transplantation" and is designed as a single-arm, single-institution, open-label study.
Rationale:
- Overexpression of WT1 in multiple myeloma (MM) cells has been demonstrated by immunocytochemistry (IHC) and in HLA-A\*0201 patients by staining with a high-affinity fully human IgG1 mAb (ESK1) specific to the RMFPNAPYL/HLA-A\*0201 complex on malignant plasma cells. WT1 also serves as a target for antigen-specific directly immunizing immunotherapeutic approaches, such as peptide vaccines (in this case, galinpepimut-S), in patients with multiple myeloma. Patients with persistent plasma cell leukemia following CD34+-selected allografts treated with adoptive transfer of donor-derived WT1-specific cytotoxic T cells are capable of achieving long-lasting complete remission (CR) status, thus underscoring the therapeutic potential of activated T-cells specifically immunized against WT1 peptides. The above provide the theoretical basis for the possibility of successful immunization after exposure to a WT1-specific vaccine (such as galinpepimut-S), whereby WT1-sensitized T-lymphocytes (both CD8+ and CD4+) from vaccinated MM could be directed to antigen (WT1) expressed on malignant plasma cells.
Galinpepimut-S (GPS) - Key features:
- GPS is a tetravalent peptide vaccine, consisting of an equiweight mixture of 4 WT1-derived peptides which have been chosen to strengthen antigenicity, but also broaden immunogenicity over a wide range of HLA subtypes, being able to stimulate both CD8+ (MHC Class I)- and CD4+ (MHC Class II)-dependent responses. Of note, 2 of the 4 peptides are heteroclitic, i.e., carry by-design introduced missense mutations, in order to decrease tolerogenicity (as these modified peptides are no longer identified as "self" moieties by the vaccinated host's immune system. GPS contains one heteroclitic peptide (WT1-A1) to stimulate CD8+ responses, two longer native peptides (427 long and 331 long) to stimulate CD4+ responses and one longer heteroclitic peptide (122A1 long) that is capable of stimulating both CD8+ and CD4+ cells (with the CD8-activating shorter sequence/locus 'buried' with the lengthier CD4-activating one). Galinpepimut-S is always mixed in emulsion with the immunological adjuvant Montanide™ and is administered after granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostine; Leukine®) pre-stimulation.
Putative Mechanism of action (MOA) of galinpepimut-S in MM:
- Galinpepimut-S (GPS) is a peptide immunogen of the vaccine type, capable of inducing in the treated host WT1-specific antigenicity and eventual systemic immunogenicity against WT1-expressing deposits of cancerous cells. The above principles are applicable in MM patients treated with this immunotherapeutic. It is very likely that the antigen presenting cell (APC)-CD8-CD4 cross-activating circuits are markedly amplified in subjects receiving galinpepimut-S, leading to specific and direct immunization against WT1 and eventual killing of WT1-expressing malignant plasma cells via activated immunocytes (mainly lymphocytes and natural killer \[NK\] cells). This MOA represents a plausible model for the immunobiological basis of the observed clinical activity of galinpepimut-S against various tumor types (other than MM) tested to-date, and is poised to be applicable in MM as well.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 22
- Symptomatic multiple myeloma, ISS stage 1-3 with confirmed diagnosis of multiple myeloma at MSKCC
- Patients must be eligible to undergo autologous stem cell transplantation by standard institutional criteria
- Patients must have documented WT1 positive disease. For purpose of this study, this is defined as detectable presence of WT1 expression by immunohistochemistry or by WT1 transcript via RT-PCR on a bone marrow or other plasma cell-related biopsy specimen prior to autologous stem cell transplantation. Bone marrow or other biopsy specimen from time of diagnosis from patients diagnosed at MSKCC or outside hospital may be requested for assessment of WT1 expression by IHC
- Age > or = to 18 years
- Karnofsky performance status > or = to 50%
- Hematologic parameters:
- Absolute neutrophil count (ANC) > or = to 1,000/μl
- Platelets > 50,000/μl
- Biochemical parameters:
- Total bilirubin < than or = to 2.0 mg/dl
- AST and ALT < than or = to 2.5 x upper limits of normal (ULN)
- Creatinine < than or = to 2.0 mg/dl
- Pregnant or lactating women
- Patients with active infection requiring systemic antimicrobials
- Patients taking systemic corticosteroids
- Patients with serious unstable medical illness
- Concurrent malignancies
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Galinpepimut-S + Montanide + GM-CSF Galinpepimut-S Galinpepimut-S (GPS) vaccinations are started 12-22 days following autologous stem cell transplantation (ASCT). GPS and Montanide (in a 1 mL emulsion) are administered subcutaneously (s.c.) Q2W on weeks 0, 2, 4, 6, 8, and 10. GM-CSF (70 μg) are administered s.c. one to two days before and on the day of GPS/Montanide administration. Participants whose disease has not progressed and who are clinically stable (no active infection with fevers and no cardiovascular/respiratory compromise) may receive up to 6 additional monthly vaccinations. The use of post-ASCT maintenance therapy is allowed starting 3 months after ASCT. Galinpepimut-S + Montanide + GM-CSF Montanide Galinpepimut-S (GPS) vaccinations are started 12-22 days following autologous stem cell transplantation (ASCT). GPS and Montanide (in a 1 mL emulsion) are administered subcutaneously (s.c.) Q2W on weeks 0, 2, 4, 6, 8, and 10. GM-CSF (70 μg) are administered s.c. one to two days before and on the day of GPS/Montanide administration. Participants whose disease has not progressed and who are clinically stable (no active infection with fevers and no cardiovascular/respiratory compromise) may receive up to 6 additional monthly vaccinations. The use of post-ASCT maintenance therapy is allowed starting 3 months after ASCT. Galinpepimut-S + Montanide + GM-CSF bortezomib Galinpepimut-S (GPS) vaccinations are started 12-22 days following autologous stem cell transplantation (ASCT). GPS and Montanide (in a 1 mL emulsion) are administered subcutaneously (s.c.) Q2W on weeks 0, 2, 4, 6, 8, and 10. GM-CSF (70 μg) are administered s.c. one to two days before and on the day of GPS/Montanide administration. Participants whose disease has not progressed and who are clinically stable (no active infection with fevers and no cardiovascular/respiratory compromise) may receive up to 6 additional monthly vaccinations. The use of post-ASCT maintenance therapy is allowed starting 3 months after ASCT. Galinpepimut-S + Montanide + GM-CSF GM-CSF Galinpepimut-S (GPS) vaccinations are started 12-22 days following autologous stem cell transplantation (ASCT). GPS and Montanide (in a 1 mL emulsion) are administered subcutaneously (s.c.) Q2W on weeks 0, 2, 4, 6, 8, and 10. GM-CSF (70 μg) are administered s.c. one to two days before and on the day of GPS/Montanide administration. Participants whose disease has not progressed and who are clinically stable (no active infection with fevers and no cardiovascular/respiratory compromise) may receive up to 6 additional monthly vaccinations. The use of post-ASCT maintenance therapy is allowed starting 3 months after ASCT. Galinpepimut-S + Montanide + GM-CSF lenalidomide Galinpepimut-S (GPS) vaccinations are started 12-22 days following autologous stem cell transplantation (ASCT). GPS and Montanide (in a 1 mL emulsion) are administered subcutaneously (s.c.) Q2W on weeks 0, 2, 4, 6, 8, and 10. GM-CSF (70 μg) are administered s.c. one to two days before and on the day of GPS/Montanide administration. Participants whose disease has not progressed and who are clinically stable (no active infection with fevers and no cardiovascular/respiratory compromise) may receive up to 6 additional monthly vaccinations. The use of post-ASCT maintenance therapy is allowed starting 3 months after ASCT.
- Primary Outcome Measures
Name Time Method WT1 T-cell Immune Response (IR) 12-14 Weeks After First GPS Administration (6 x Administrations) 12 weeks after the initial GPS vaccine (end of first series [GPS x 6 administrations]) Number and percentage of participants with CD4 and/or CD8 immune responses against WT1m measured 12-14 weeks after first GPS administration (6 x administrations)
- Secondary Outcome Measures
Name Time Method Progression-free Survival (PFS) From Autologous Stem Cell Transplant (ASCT) 3 years and 8 months PFS measured from ASCT to time of myeloma progression (as defined by the International Myeloma Working Group \[IMW\] consensus criteria or subject death.
Overall Survival (OS) From Autologous Stem Cell Transplant (ASCT) 3 years and 8 months OS measured from time of autologous stem cell transplant (ASCT) to the time of subject death
Trial Locations
- Locations (1)
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States