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Clinical Trial
. 2011 Jan 20;117(3):788-97.
doi: 10.1182/blood-2010-08-299396. Epub 2010 Oct 28.

Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma

Aaron P Rapoport  1 , Nicole A Aqui, Edward A Stadtmauer, Dan T Vogl, Hong-Bin Fang, Ling Cai, Stephen Janofsky, Anne Chew, Jan Storek, Gorgun Akpek, Ashraf Badros, Saul Yanovich, Ming T Tan, Elizabeth Veloso, Marcela F Pasetti, Alan Cross, Sunita Philip, Heather Murphy, Rita Bhagat, Zhaohui Zheng, Todd Milliron, Julio Cotte, Andrea Cannon, Bruce L Levine, Robert H Vonderheide, Carl H June
Affiliations
Clinical Trial

Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma

Aaron P Rapoport et al. Blood. .

Abstract

In a phase 1/2 two-arm trial, 54 patients with myeloma received autografts followed by ex vivo anti-CD3/anti-CD28 costimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a multipeptide tumor antigen vaccine derived from the human telomerase reverse transcriptase and the antiapoptotic protein survivin. Patients negative for human leukocyte antigen A2 (arm B, n = 26) received the pneumococcal conjugate vaccine only. Patients exhibited robust T-cell recoveries by day 14 with supraphysiologic T-cell counts accompanied by a sustained reduction in regulatory T cells. The median event-free survival (EFS) for all patients is 20 months (95% confidence interval, 14.6-24.7 months); the projected 3-year overall survival is 83%. A subset of patients in arm A (36%) developed immune responses to the tumor antigen vaccine by tetramer assays, but this cohort did not exhibit better EFS. Higher posttransplantation CD4(+) T-cell counts and a lower percentage of FOXP3(+) T cells were associated with improved EFS. Patients exhibited accelerated polyclonal immunoglobulin recovery compared with patients without T-cell transfers. Adoptive transfer of tumor antigen vaccine-primed and costimulated T cells leads to augmented and accelerated cellular and humoral immune reconstitution, including antitumor immunity, after autologous stem cell transplantation for myeloma. This study was registered at www.clinicaltrials.gov as NCT00499577.

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Figures

Figure 1
Figure 1
Trial design. CMV indicates cytomegalovirus.
Figure 2
Figure 2
Kaplan-Meier survival curves. (A) Overall survival. (B) Event-free survivals (EFS) according to assignment to study arm. EFS for arm B is superior to EFS for arm A (P = .0068). (C) EFS for patients who remained event-free at day 180 after transplantation and received thalidomide maintenance had improved EFS compared with patients who did not receive thalidomide (P = .0089).
Figure 3
Figure 3
Tetramer immune responses to hTERT/survivin vaccine. (A) Bar graph showing 10 patients (of 28; 36%) with positive tetramer responses defined as > 3-fold increase in tetramer staining compared with enrollment/baseline and minimum level of 0.1%. (B) Same patients depicted in panel A but using an expanded y-axis to show the full spectrum of responses.
Figure 4
Figure 4
Functional immune responses in specific patients. (A) Deep skin biopsy of ≥ 5-cm area of induration (from patient MD012) showing CD8+/CD3+ T-cell infiltrate. (B) Tetramer analysis of T cells extracted from the skin biopsy depicted in panel A; 2.1% of the cells analyzed exhibited hTERT/survivin tetramer staining versus 0.1% in the control (tetramer negative) sample. (C) Proliferative response of CD8+ T cells (from patient UPCC/13406-11) after stimulation with hTERT/survivin peptide mix by CFSE dilution analysis; percentage of CFSEdim was 11.2% in the hTERT/survivin-stimulated cells (bottom) versus 6.67% in cells stimulated with an irrelevant peptide derived from the Tax protein (top) and 6.2% in cells exposed to medium only (data not shown). (D) Proliferative response of CD8+ T cells from a second immunized patient (UPCC/13406-22) after stimulation with hTERT/survivin peptide mix by CFSE dilution analysis; percentage of CFSEdim was 33.2% in the hTERT/survivin-stimulated cells (bottom) versus 11.7% in cells that were incubated in media only without peptide stimulation (top).
Figure 5
Figure 5
B- and T-cell responses to PCV vaccine. (A) Log-transformed plot of mean serum IgG antibody responses for each of the 4 PCV serotypes tested over the course of the study. (B) CD4+ T-cell responses to the CRM-197 carrier protein on the basis of proliferation assays with the use of CFSE dilution; percentage of CFSEdim cells after CRM-197 stimulation at various time points for 49 total patients are shown. Black circles indicate nonresponders; red circles, responders. A responder is defined as a patient having at least a 3-fold increase of the enrollment measurement at ≥ 1 posttransplantation time points.
Figure 6
Figure 6
Immune reconstitution with sustained lymphocytosis of multiple T-cell subsets after transplantation. (A) Mean CD3+, CD4+, and CD8+ counts at various time points before and after transplantation. EN indicates enrollment; TCH, T-cell harvest (apheresis); TR, transplantation date. (B) Mean levels of CD4+ subsets before and after transplantation. Bars denote the standard errors.
Figure 7
Figure 7
Percentage of CD4+FOXP3+ T cells and Teff/Treg ratio before and after transplantation. (A) Percentage of CD4+FOXP3+ T cells at various time points before and after transplantation. Bars denote 1 standard deviation. (B) Loge of Teff/Treg ratio at various time points before and after transplantation. EN indicates enrollment; TCH, T-cell harvest (apheresis).
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