Phase I/II Combination Immunotherapy After ASCT for Advanced Myeloma to Study HTERT Vaccination Followed by Adoptive Transfer of Vaccine-Primed Autologous T Cells
- To evaluate the safety of combination immunotherapy using activated T-cells and an
hTERT/survivin multipeptide vaccine in the post-autotransplant (autologous stem cell
transplantation) setting and whether it delays hematopoietic recovery or induces
- To determine whether the strategy of infusing vaccine-primed T-cells early after
transplant in conjunction with post-transplant booster immunizations leads to the
induction of cellular immune responses to the putative tumor antigens hTERT ( the
catalytic subunit of telomerase) and survivin.
- To determine if combination immunotherapy as delivered to arm I patients increases the
frequency of delayed paraprotein responses between 60 days and 6 months
post-transplant, sufficient to upgrade the maximal level of myeloma response, when
compared to non-vaccinated (arm II) patients.
- To determine if adoptive transfer of hTERT/survivin-primed T-cells in conjunction with
multi-peptide booster immunizations generates cytotoxic T-cell responses to autologous
myeloma cells in vivo.
- To evaluate myeloma clinical responses including the frequency of complete and partial
responses and the 1 & 2-year event-free and overall survivals.
- To measure antibody responses to 4 of the 7 serotypes contained in the pneumococcal
polyvalent vaccine as well as T-cell responses to the CRM-197 carrier protein and to a
CMV peptide antigen.
- To evaluate levels of hTERT and survivin expression in patient myeloma cells.
OUTLINE: This is a multicenter study. Patients are stratified according to HLA-A2 status
(positive vs negative). Patients are assigned to 1 of 2 treatment groups based on
- Immunization 1:
- Group 1 (HLA-A2 positive): Patients receive the following peptides emulsified in
incomplete Freund's adjuvant VG: I) hTERT I540 peptide; ii) hTERT R572Y peptide;
iii) hTERT D988Y peptide; iv) survivin Sur1M2 peptide ; and v) CMV control peptide
N495 subcutaneously (SC). Patients also receive sargramostim (GM-CSF) SC and
pneumococcal conjugate vaccine (PCV) intramuscularly (IM).
- Group 2: Patients receive PCV vaccine IM and GM-CSF SC.
- Steady-state T-cell harvesting:About 10 days (range 7-14) after immunization #1, all
patients undergo a mononuclear cell apheresis procedure to collect steady-state T-cells
that are cryopreserved for later expansion.
- Stem cell mobilization: After completion of the mononuclear cell apheresis procedure,
all patients are offered DT-PACE chemotherapy for cytoreduction and stem cell
mobilization. This regimen is as follows: dexamethasone once daily for 4 days;
thalidomide once daily for 4 days; cisplatin IV continuously over 4 days (patients with
serum creatinine levels ≥ 2.0 mg/dL do not receive cisplatin); doxorubicin
hydrochloride IV continuously over 4 days; cyclophosphamide IV continuously over 4
days; etoposide IV continuously over 4 days. Patients also receive filgrastim (G-CSF)
SC once daily starting on the day after completion of chemotherapy. An acceptable
alternative for stem cell mobilization is to use cyclophosphamide IV over 12 hours or,
for patients who require that outpatient stem cell mobilization procedures be
performed, cyclophosphamide IV over 2 hours. The cyclophosphamide mobilization regimen
should be used if the patient has already received DTPACE as part of the pre-transplant
- High-dose therapy: High-dose therapy will consist of melphalan IV over 20 minutes on
day -1. Autologous stem cell infusion takes place on day 0, at least 18 hours after the
administration of the high-dose melphalan. Stem cells are infused IV over 20-60
minutes. G-CSF SC should be administered beginning on day +5.
- Autologous T-cell expansion and infusion: Cryopreserved cells are expanded ex vivo for
up to 12 days and prepared for infusion on day 2 post-transplant.
- Infusion of autologous T-cells: The costimulated ("activated") T-cells are infused over
20-60 minutes on day +2 of transplant.
- Immunizations 2, 3, and 4:
- Group 1: On days 14, 42, and 90 post-transplant, patients receive peptides, PCV,
and GM-CSF as in group I of immunization # 1.
- Group 2: On day 14, 42, 90 post-transplant, patients receive PCV and GM-CSF as in
group II of immunization # 1.
- Maintenance therapy: At day 180 post-transplant, after completion of post-transplant
immunological assessments, patients receive low-dose thalidomide in the absence of
disease progression or unacceptable toxicity.
Blood is collected at T-cell harvest and days 14, 60, 100, and 180 post-transplant. Samples
are analyzed by quantitative CD3/CD4/CD8 studies, cellular immunoassays, antibody
immunoassays, and gene expression.
After completion of study treatment, patients are followed periodically.
Primary Purpose: Treatment
Toxicity at 21 and 28 days post-transplant
Aaron P. Rapoport, MD
University of Maryland Greenebaum Cancer Center
United States: Food and Drug Administration
|Abramson Cancer Center of the University of Pennsylvania||Philadelphia, Pennsylvania 19104-4283|
|Greenebaum Cancer Center at University of Maryland Medical Center||Baltimore, Maryland 21201|