Cellular Therapy

A phase I/II minor histocompatibility antigen-loaded dendritic cell vaccination trial to safely improve the efficacy of donor lymphocyte infusions in myeloma

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Allogeneic stem cell transplantation (allo-SCT) with or without donor lymphocyte infusions (DLI) is the only curative option for several hematological malignancies. Unfortunately, allo-SCT is often associated with GvHD, and patients often relapse. We therefore aim to improve the graft-versus-tumor effect, without increasing the risk of GvHD, by targeting hematopoietic lineage-restricted and tumor-associated minor histocompatibility antigens using peptide-loaded dendritic cell (DC) vaccinations. In the present multicenter study, we report the feasibility, safety and efficacy of this concept. We treated nine multiple myeloma patients with persistent or relapsed disease after allo-SCT and a previous DLI, with donor monocyte-derived mHag-peptide-loaded DC vaccinations combined with a second DLI. Vaccinations were well tolerated and no occurrence of GvHD was observed. In five out of nine patients, we were able to show the induction of mHag-specific CD8+ T cells in peripheral blood. Five out of nine patients, of which four developed mHag-specific T cells, showed stable disease (SD) for 3.5–10 months. This study shows that mHag-based donor monocyte-derived DC vaccination combined with DLI is safe, feasible and capable of inducing objective mHag-specific T-cell responses. Future research should focus on further improvement of the vaccination strategy, toward translating the observed T-cell responses into robust clinical responses.


Allogeneic stem cell transplantation (allo-SCT) with or without donor lymphocyte infusions (DLI) can induce durable remissions due to an allogeneic graft-versus-tumor (GVT) effect.1 In an HLA-matched setting, this effect is mainly mediated by donor-derived T cells directed against recipient’s minor histocompatibility antigens (mHags) present on malignant cells.2 Unfortunately, allo-SCT is frequently associated with severe, sometimes life-threatening GvHD. In addition, patients may relapse after achieving an initial remission, underscoring the need for novel strategies to improve the efficacy and specificity of allo-SCT and DLI. There is compelling evidence that the induction of GVT and GvHD crucially depends on the presence of professional antigen-presenting cells, in particular dendritic cells (DCs), capable of presenting host antigens.3, 4 It has been postulated that accomplishing strong and specific GVT effects could be possible through vaccination of allotransplanted patients with DCs, capable of presenting tumor-associated host antigens to donor T cells. We and other investigators previously evaluated host DC vaccinations and tumor-associated antigen-loaded DC vaccination after allo-SCT.5, 6, 7, 8, 9, 10 Thus far, these studies revealed that host- or donor-DC vaccination after allo-SCT, combined with DLI, is feasible, safe and can induce relevant tumor-associated immune responses. Encouraged by the initial studies, we evaluated in a multicenter phase I/II trial the feasibility, safety and clinical efficacy of treatment of DLI non-responders with a second equivalent dose of DLI combined with a DC vaccine, which was generated from donor monocytes and pulsed with peptides of hematopoietic-restricted mHags.


Patients and definitions

The study was approved by the Dutch Central Committee on Research Involving Human Subjects (CCMO, ABR 39604, trial EudraCT number: 2012-002435-28) and conducted according to the Declaration of Helsinki after informed consent of patients and donors.

Candidates for the study were HLA-A2, -A24, -B7 and/or -B44-positive patients aged 18 years, who did not respond to DLI given for relapsed or residual disease after an HLA-matched allo-SCT. Included were patients who showed at least one mismatch with their donors for the hematopoietic-restricted mHags HA-1, HA-2, UTA2-1, LRH-1, ACC-1, ACC-2, PANE-1 and HB-1 in the GVT direction (that is, patient positive, donor negative for the mHag).11 Main exclusion criteria were WHO performance 3–4, rapidly progressive disease despite salvage treatment, concomitant use of immunosuppressive drugs and the presence of acute GvHD >grade 1 or extensive chronic GvHD. Maintenance therapy was allowed, but could not be started prospectively after DLI. Patients on maintenance therapy had to have stable disease (that is, no ongoing response on maintenance) to allow assessment of the response to the study treatment. Included patients received an equivalently dosed subsequent DLI combined with DC vaccination. Patients received a total dose of 45–90 × 106 DCs, administered in three vaccinations with 2-week intervals. In each vaccination, two out of three of the DCs were administered IV and one out of three intradermal in the median site of the upper leg. The first DC administration was combined with the DLI. Response assessment was performed at week 14 and total follow-up was until week 20. Response criteria were based on the International Myeloma Working Group uniform response criteria.12, 13 Furthermore, for selected patients, plasma cell chimerism was determined in freshly FACS purified bone marrow plasma cells using a previously reported method and used as an additional marker of disease activity.14 Time to progression was defined as time between the start of the first DC vaccination and the occurrence of progression or relapse. Toxicity was assessed using the latest available version of common toxicity criteria for adverse events (version 4.0). The GvHD assessment was done using IBMTR criteria, which classifies GvHD according to percentage of involved skin surface, level of serum bilirubin and amount of diarrhea in mL per day in four classes.15

Vaccine generation

The DC vaccine was generated using a 9-day culture protocol under good manufacturing practice conditions from CD14+ monocytes enriched from a leukapheresis product of the original stem cell donor. Isolation of CD14+ monocytes was done using a CliniMACS procedure. After enrichment, DCs were cultured in X-Vivo 15 medium supplemented with 2% human serum in the presence of GM-CSF (800 IU/mL) and IL-4 (500 IU/mL). After 3 days, fresh medium with GM-CSF and IL-4 was added, together with keyhole limpet hemocyanin (KLH) protein (20 μg/mL). At day 7, the DCs were matured ex vivo using IL-6 (15 ng/mL), IL-1β (5 ng/mL), TNFα (600 IU/mL) and PGE-2 (1 μg/mL). At day 9, the mature DCs were then pulsed with 10 μg/mL of the appropriate mHag peptide for 2.5–3 h, after which the cells were washed. The peptide-loaded, mature DCs were then cryopreserved for quality control testing and release until administration. Cryopreservation had no effect on the antigen-presenting capacity of the DCs.10 Patients received a total dose of 45–90 × 106 peptide-loaded DCs, administered in three vaccinations with 2-week intervals. A reference vial was thawed and used for quality evaluation determining sterility (endotoxin levels <1.6 IU/mL; negative for anaerobic and aerobic bacteria, fungi and yeast), viability (>70% is 7AAD− on flow cytometry or trypan blue negative on light microscopy), purity (<30% expression of CD3 (BD Biosciences, San Jose, CA, USA), CD14 (Beckman Coulter, Woerden, Netherlands), CD66e (Sanquin, Amsterdam, Netherlands), CD19 (Beckman Coulter) and CD56/16 (BD Biosciences)) and maturity (>70% of the CD11c+ (BD Biosciences) DCs express CD80, CD86, CD83 (all BD Biosciences) and HLA-DR (Biolegend, London, UK)). Vaccines were manufactured locally at the two participating centers.

Immune monitoring

Next to mHag peptides, the DCs were also loaded with the MHC class II-restricted protein KLH as an adjuvant to provide CD4+ T-cell help for boosting cytotoxic CD8+ T-cell responses, and to monitor immunological responses after vaccination. Peripheral blood mononuclear cells (PBMC) samples obtained from week 0 (baseline), weeks 1, 2, 4, 6, 8, 10, 14 and week 20 (end of follow-up) after vaccination were incubated in vitro with 5 μg/mL of KLH peptide for 5 days. After 5 days, cells were washed and proliferation was analyzed by staining with Cell Trace Violet Cell Proliferation Kit (ThermoFisher) and expressed as percentage of divided cells/total CD3+ T cells, as measured on a FACS Canto II (BD Biosciences). Activation was measured by staining the PBMCs for CD25, CD38 and HLA-DR, and depicted as the percentage of CD3+ T cells expressing CD25 or co-expressing CD38/HLA-DR (all antibodies from BD Biosciences). In addition, the presence of mHag-specific CD8+ T cells was determined on the obtained PBMC samples. mHag-specific CD8+ T cells were identified as viable (SYTOX blue negative, ThermoFisher), CD45+ cells double positive for antigen-presenting cell and PE peptide-MHC tetramers within the CD3+ CD8+ population.


Patient and vaccine characteristics

Between May 2014 and 2016, nine MM patients were included in the University Medical Center Utrecht and the Radboud University Medical Center. Because of pre-defined stopping rules, inclusions were stopped after the nineth patient due to limited efficacy. Patients had a median age of 56 years (range, 40–66) and were heavily pretreated with a median number of previous treatment lines of five (range, 4–7) (Table 1). Patients were intended to receive a minimal dose of 45 × 106 and a maximum of 90 × 106 DCs. From all donors, we were able to generate sufficient mHag-loaded, pure and highly mature DCs (Table 2). The lowest number of DCs administered was 64 × 106. The vaccine was administered in three courses with 2-week intervals. In each vaccination, two out of three of the DCs were administered IV and one out of three intradermal in the median site of the upper leg. The first DC administration was combined with a DLI. None of the included patients had rapidly progressive disease requiring salvage treatment before DLI. Patient 9 mistakenly received a DLI dose of 40 × 106 instead of 5 × 106, which was reported as a protocol violation. This did not lead to any toxicity.

Table 1 Patient characteristics and outcome
Table 2 Generation and characteristics of the DC vaccines

Induction of peptide-specific T cells

Analysis of collected PBMC samples showed a rapid induction of anti-KLH responses in all patients after the first vaccination, as shown by in vitro proliferation and activation of T cells upon incubation with KLH (Figure 1a). However, in seven out of nine patients, these responses were lower after the second and third vaccination. Analyses of several T-cell subsets, including CD4+, CD8+ and regulatory T cells did not reveal significant changes after vaccination (Supplementary Data). Flow cytometric analyses of PBMCs with mHag peptide-MHC tetramers showed the induction of mHag-specific CD8+ T cells in five out of nine patients, with the highest frequency in patient 6 (Figures 1b and c). The percentage and time interval of occurrence varied between patients (Figure 1c).

Figure 1

mHag-loaded donor DC vaccinations induce anti-KLH responses and mHag-specific T cells in peripheral blood. (a) KLH-specific T-cell proliferation and activation is induced by mHag and KLH-loaded donor-derived DC vaccines. Vaccinations were administered at week 0, 2 and 4. DLI was administered at week 0. Shown are pooled data of nine patients, mean±s.e.m. (b) Gating strategy of mHag-reactive CD8 T cells. The presence of mHag-specific T cells was defined as the percentage of viable (SYTOX blue negative, ThermoFisher), CD45+ cells double positive for antigen-presenting cell and PE peptide-MHC tetramers within the CD3+ CD8+ population. (c) Different patterns and variable levels of induced mHag-specific T cells after vaccination were observed. Vaccinations were administered at weeks 0, 2 and 4. DLI was administered at week 0. Results for five individual patients are shown.

Clinical response

Response assessment was performed at week 14 and total follow-up was until week 20. No objective clinical responses (PR) were observed (Table 1). Median time to progression was 3.5 months (range, 1–10). Three patients were included with progressive disease (patients 3, 7 and 8). All of these patients showed ongoing progression after vaccination. Five patients remained in stable disease for a median of 7 months after vaccination (Pt 1, 4, 5, 6 and 9) (patient 6 still without signs of progression, although on maintenance treatment, patients 1, 4, 5 and 9 have all progressed). Patient 2, included with minimal residual disease (determined by chimerism analysis on purified plasma cells), received radiotherapy on a bone lesion 2.2 months after inclusion, and achieved a complete molecular remission with 100% donor plasma cell chimerism shortly thereafter, and has remained in complete molecular remission for 23 months now.


The vaccinations were well tolerated with only transient induration and erythema at the intradermal injection site and grade 2 fever after the second and third vaccination, lasting less than 24 h, in all patients. There was no development of GvHD or any life-threatening toxicity. Five severe adverse events were reported, four being possibly related to the vaccinations: one admission because of high fever and abdominal pain after the second vaccination, which resolved spontaneously, and three admissions with pneumonia. Other adverse events consisted of diarrhea causing hypophosphatemia, flu-like symptoms, liver enzyme elevation, herpes simplex infection and a basal cell carcinoma of the skin. All adverse events were common toxicity criteria grade II or III.


This study demonstrates the feasibility, safety and efficacy of mHag-peptide-loaded donor DC vaccination combined with DLI in patients with persistent or relapsed disease after allo-SCT and previous DLI. To our knowledge, we are the first to describe the use of donor-derived DCs loaded with mHag peptides as vaccines in combination with DLI.

In the few vaccination studies performed in the allo-SCT setting, DCs were loaded with various antigens using different techniques. The source of DCs (autologous or allogeneic) also differed.5, 6, 7, 8, 9 Thus far, all these studies have shown that the vaccinations were safe and well tolerated. In none of the studies, except in one of our previous studies with autologous DCs,10 DC vaccination was combined with a second equivalently dosed DLI. We chose this strategy because T cells from the first DLI, as they did not induce any sustainable GVT effect, could have been anergized or dysfunctional, which is often the case in MM patients.16, 17, 18, 19, 20 We did not increase the dose of the DLI with the idea that the effect of the first DLI could serve as a control for the effect of combinatorial DLI+DC vaccination. Several other decisions in the design of this study, such as the dose, administration intervals and administration route (IV+ intradermal) were based on our previous experience10, 21 with the intention to keep the variation between this and previous studies minimal. Nevertheless, it could well be that in a different design the outcome of DC vaccination in these patients could have been different. Therefore, the results of this study need to be interpreted within its specific design.

In agreement with our previous results, we observed a low toxicity from mHag peptide pulsed donor DC vaccinations, even after combination with a second DLI, demonstrating the safety of the approach. The observed immunological responses in this trial are also in line with previous studies and provide evidence for the capacity of mHag-peptide-loaded DCs to induce or boost tumor-reactive cytotoxic T lymphocytes (CTLs). Nonetheless, in virtually all previous studies, not all patients developed CTLs. Although it is not well understood why some patients do and some do not mount a CTL response, we can exclude DC-related factors, because the quality of the DCs was more or less equal in all vaccine products.

Disease characteristics could also be of influence: We observed that in our study, three out of four patients who failed to induce CTLs (Pt 7, 8 and 9) entered the study with a response status of PR or progressive disease, while such patients represented only one out of five in the group who did develop CTLs upon vaccination. Although these differences did not reach statistical significance it may be, if possible, better not to include patients with a progressive disease in future trials.

Besides mHag-specific CTL induction, our main goal was to induce clinical responses. In this study, we observed that the developed CTL responses did not translate into robust clinical responses and even the induction of a considerably high frequency of mHag UTA2-1-specific CTLs in one patient (Pt 6) did not translate into a clear clinical response. Although not statistically significant, we noted that four out of five patients (Pt 1, 4, 5 and 6) who developed mHag-reactive CTLs after vaccinations had a longer time to progression than expected, while the time to progression of the patients who did not develop mHag-specific CTLs was much shorter. These observations trigger the discussion why the clinical effects of our induced CTLs were not, or at best were hardly, visible. Among several possibilities, one could speculate on the limited persistence of the induced T-cell responses. Are monocyte-derived DCs not capable of inducing stable CTLs? Or are the induced CTLs quickly inactivated?

Although these mechanisms need to be further elucidated in future trials, it seems highly plausible that the expansion or even the cytotoxic function of tumor-specific CTLs could be actively suppressed by tumor (microenvironment)-related factors. In this respect, several well-described suppressive cytokines (for example, TGF-β and IL-10), immune cells (for example, regulatory T cells and myeloid-derived suppressor cells) and immune-checkpoint molecules, such as PD-L1, could play a role.22, 23 Regarding the latter, we have previously shown that the presence of immune-checkpoint molecules on DCs hampers sufficient priming and boosting of mHag-specific T cells.24, 25 Importantly, siRNA-mediated silencing of PD-1 ligands on DCs increases the immunogenicity of the vaccine and thereby boosts the induction of mHag-specific T-cell responses.26, 27 A similar scenario is plausible when effector CTLs encounter PD-L1+ tumor cells. Thus, as already suggested by others, the use of systemic immune-checkpoint inhibitors may improve the outcome of DC vaccination, but has to be used with caution in combination with DLI due to the potential risk of eliciting severe GvHD.28, 29

In addition to these possible future perspectives, our current results point out that patient selection for vaccination strategies is crucial. Patients with a low tumor burden and stable disease are the best candidates for immune therapy with DCs. But even in these patients, our focus should be on strategies targeting tumor-induced immune suppression, to overcome this important barrier to effective anti-tumor immune therapy.

In conclusion, our findings demonstrate that mHag-based donor-derived DC vaccination is safe and well tolerated when combined with DLI. In addition, this strategy is capable of inducing objective mHag-specific T-cell responses. These findings warrant future investigations, focusing on improvement of the vaccination strategy, toward translating the observed T-cell responses into robust clinical responses.


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Correspondence to L E Franssen.

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Franssen, L., Roeven, M., Hobo, W. et al. A phase I/II minor histocompatibility antigen-loaded dendritic cell vaccination trial to safely improve the efficacy of donor lymphocyte infusions in myeloma. Bone Marrow Transplant 52, 1378–1383 (2017) doi:10.1038/bmt.2017.118

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