Abstract
The potential for the immune system to target hematological malignancies is demonstrated in the allogeneic transplant setting, where durable responses can be achieved. However, allogeneic transplantation is associated with significant morbidity and mortality related to graft versus host disease. Cancer immunotherapy has the capacity to direct a specific cytotoxic immune response against cancer cells, particularly residual cancer cells, in order to reduce the likelihood of disease relapse in a more targeted and tolerated manner. Ex vivo dendritic cells can be primed in various ways to present tumor associated antigen to the immune system, in the context of co-stimulatory molecules, eliciting a tumor specific cytotoxic response in patients. Several approaches to prime dendritic cells and overcome the immunosuppressive microenvironment have been evaluated in pre-clinical and early clinical trials with promising results. In this review, we summarize the clinical data evaluating dendritic cell based vaccines for the treatment of hematological malignancies.
Abbreviations
| CTLA-4 | = | Cytotoxic T-Lymphocyte Antigen 4 |
| PD-L1 | = | Programmed death-ligand 1 |
| PD-1 | = | Programmed death 1 |
| DNA | = | Deoxyribonucleic acid |
| RNA | = | Ribonucleic acid |
| ASCT | = | Autologous Stem Cell Transplant |
| OS | = | Overall Survival |
| Id | = | Idiotype |
| IL | = | Interleukin |
| CML | = | Chronic Myeloid Leukemia |
| WT-1 | = | Wilm's tumor suppressor gene 1 |
| AML | = | Acute Myeloid Leukemia |
| mRNA | = | mRNA |
| GMCSF | = | Granulocyte macrophage colony-stimulating factor |
| MDS | = | Myelodysplastic syndrome |
| GVHD | = | Graft vs Host Disease |
| SCT | = | Stem cell transplant |
| KLH | = | Keyhole limpet hemocyanin |
| Apo-DC | = | Apoptotic body loaded- dendritic cells |
| IFN | = | Interferon |
| IFNg | = | Interferon gamma |
| HLA-A*2402 | = | Human Leukocyte antigen A*2402 |
| CR | = | Complete response |
| PR | = | Partial response |
| DC/MM | = | Dendritic cell Multiple Myeloma fusion vaccine |
| VGPR | = | Very good partial response |
| DC/AML | = | Dendritic cell Acute Myeloid Leukemia fusion vaccine |
| FLT-ITD | = | Fms-like Tyrosine Kinase with Internal Tandem Duplication |
| VEGF | = | Vascular endothelial growth factor |
| TGFB | = | Transforming growth factor β |
| pDCs | = | Plasmacytoid Dendritic cell |
| TNFα | = | Tumor necrosis factor α |
| PRR | = | Pathogen recognition receptor |
| MHC | = | Major histocompatibility complex |
Introduction
While cytotoxic chemotherapy can effectively reduce a patient's tumor burden at the time of presentation, patients typically suffer significant treatment related toxicities due to the non-specific effects of these drugs.Citation1 Furthermore, patients often subsequently succumb to relapsed disease, thought to be due to residual cancer cells that are inherently resistant to traditional cytotoxic therapy.Citation2 Cancer immunotherapy has the capacity to simultaneously overcome these 2 problems, directing a specific cytotoxic immune response against cancer cells, particularly residual cancer cells, in order to reduce the likelihood of disease relapse in a more targeted and tolerated manner.Citation3
The advent of allogeneic bone marrow transplantation in the 1960s, with its potent and in some cases curative graft vs. disease effect,Citation4 further demonstrated the potential of the immune system to eliminate malignant cells. In the setting of leukemia, it has been demonstrated that the risk of disease relapse following allogeneic transplantation is inversely related to the development of graft versus host disease, demonstrating both the potency and toxicity of alloreactive lymphocytes.Citation5 Moreover, relapsed disease following allogeneic transplantation can be eradicated in a subset of patients by the infusion of donor derived lymphocytes.Citation6 However graft vs. host disease remains a major cause of morbidity and mortality following allogeneic transplantation. As such, immunotherapeutic approaches that may generate tumor specific immunity have the potential to dramatically improve outcomes of patients with hematologic malignancies.
A number of factors contribute to the ability of tumor cells to evade immune recognition. Tumor cells present antigens in the relative absence of co-stimulatory molecules such as CD80 and CD86Citation7,8 required for the activation of effector T cells, resulted in a blunted T cell response. Secondly, the immunosuppressive tumor micro-environment consisting of increased numbers of T-regulatory cells,Citation9 myeloid derived suppressor cellsCitation10and the up-regulation of the CTLA-4 and PDL-1/PD-1 negative co-stimulatory pathwaysCitation11,12 is permissive to growth and survival of malignant cells. Furthermore, malignant cells can inhibit the function of antigen presenting cells such as dendritic cells, by polarizing them to a tolerogenic phenotype.Citation13
The development of an effective cancer vaccine requires effective presentation of tumor antigen in the context of co-stimulation that is necessary for effective T cell activation, and the concurrent reversal of the immunosuppressive milleu characteristic of patients with malignancy, in order to favor the induction of long-term immunity.
Dendritic Cell Vaccines
Dendritic cells are a heterogeneous population of bone marrow derived immune cells with potent antigen presenting abilities.Citation14-16 Crucially, dendritic cells strongly express the co-stimulatory molecules required to induce primary immunity.Citation15 Ex vivo studies have demonstrated the ability of dendritic cells to interact with foreign antigens and present these to naïve CD4+ T cells, generating a clonal expansion of effector T cells.Citation16 In addition, mature dendritic cells secrete chemokines attracting B cells, resulting in the generation of a memory B cells specific to that antigen.Citation17 While dendritic cells in cancer patients are quantitativelyCitation18 and functionally deficient,Citation19 functionally potent dendritic cells can be generated from adherent peripheral blood mononuclear cells isolated from patients with malignancy by ex-vivo by culture in the presence of cytokines. As such, dendritic cells manipulated to present tumor antigen have the potential to elicit potent anti-tumor immunity.
CD14+ monocytes represent an abundant and readily accessible source of precursor cells for DC generation. Activation and maturation of DCs leads to the upregulation of co-stimulatory molecules, lymph node homing chemokines such as CCR7, and major histocompatibility complex(MHC) molecules, necessary for activation of T- and B-cells. In vivo the signal for activation and maturation comes from direct contact with pathogens or tissue endothelium, but this can be mimicked in vitro by incubation with prostaglandin E2, pathogen recognition receptor(PRR) agonists or cytokines like TNF-α.Citation20-21 The source of dendritic cells may be either autologous or allogeneic to the patient. The use of allogeneic dendritic cells has the potential to overcome the quantitative and functional deficits of dendritic cells in patients with malignancy, although is limited by dependency on the inconsistent expression of MHC class I molecules on the tumor. Studies using allogeneic dendritic cells in renal cancerCitation22,23 and B-CLLCitation24 have demonstrated the feasibility of this method.
Antigen loading
A variety of strategies for loading tumor antigens onto dendritic cells have been evaluated in clinical studies, including approaches that present individual peptides, protein, or whole tumor cell antigen in the context of the co-stimulatory machinery of the DC. Previous efforts have investigated the used of (i) peptide based vaccines,Citation25 often with an immune adjuvant,Citation26(ii) DNACitation27-29 or RNA codingCitation30,31 for a specific antigen,(iii) viral/fungal vectors expressing cancer antigensCitation32-34 or tumor apoptotic bodies.Citation35 Ex vivo data has shown varying immunogenic responses to these techniques and some of the limitations proposed have been the need for HLA matching of peptide based approaches, potentially low immunogenicity of the chosen antigen and also the possibility that tumors could develop resistance to the vaccine by down regulating the antigen in question.Citation36,37 A strategy to overcome these limitations has been the use of the whole tumor cell as a source of antigen, although there remains a risk of the induction of autoimmunity by the presentation of large volumes of self-antigen.Citation37-38
Methods for priming of DCs with whole tumor have included the whole intact tumor cell,Citation39 cell lysate,Citation40,41 apoptotic bodies,Citation42,43 microvesicles such as exosomesCitation44 and blebs, or whole cell DNA or RNA.Citation40,45 Another interesting approach has been to target antigens toward dendritic cells in vivo, by linking antigens to nanoparticles known to be captured by dendritic cells.Citation46 Our group has focused on a whole cell vaccine approach whereby patient derived tumor cells are fused to autologous, ex-vivo generated dendritic cells by co-culture in the presence of polyethylene glycol.
Considerations in administration
The route of administration influences the migration of dendritic cell based therapies to lymph nodes where they can interact with T cells. Most clinical trials have focused on subcutaneous or intradermal administration of therapies. While some pre-clinical studies have experimented with injecting DCs into the lymphatic system, ensuring that most of the DCs reach the lymph nodes, no difference in the frequency of tetramer-specific T cells could be detected between intradermal and intra lymphatic administrations.Citation47
In our group's experience of 17 patients vaccinated intradermally with a DC/myeloma fusion vaccine, 13 patients exhibited injection-site reactions after vaccination. Biopsy of these areas demonstrated a dense CD8+ mononuclear cell infiltrate suggesting recruitment and education by the DC/MM fusions at the site of vaccination. Furthermore, the presence of CD1a cells was observed in the vaccine bed, suggesting that native Langerhans cells, perhaps recruited by the presence of GM-CSF might participate in the vaccine response.Citation48
Clinical Trials Evaluating Dendritic Cell Vaccines in Hematologic Malignancies
Dendritic cell vaccines using tumor derived protein
Building on successful feasibility studiesCitation49 Timmerman et al reported the results of their phase II trial pulsing the idiotype portion of the B cell immunoglobulin with dendritic cells in patients with follicular lymphoma,Citation50 after induction of first remission, with standard of care chemotherapy. Of 35 patients treated, 65% mounted T-cell proliferative anti-idiotype responses and while complete remission was observed only in 20% of patients, long-term follow-up of patients vaccinated during first remission showed that 16 of 23(70%) remained progression free at a median of 43 months after the completion of chemotherapy. Subsequent to this, the first randomized controlled trial of dendritic cell:idiotype vaccination was reported by Schuster et al in 2009. In this study, 177 patients with untreated follicular lymphoma were randomized to receive vaccination or placebo. Median time to relapse after randomization for the experimental arm was 44.2 months versus 30.6 months for the control arm(p = 0.045; HR = 0.62).Citation51 In 2009, Lacy et al. reported a phase II trial of dendritic cell vaccination in multiple myeloma, whereby 27 patients with at least stable disease post ASCT were given 4 doses of a vaccine made by incubating dendritic cells with a serum containing autologous monoclonal protein. While there was not a difference in progression free survival between vaccine treated patients and historical controls, there was a statistically significant improvement in overall survival with vaccination,(median OS was-5.3 years in vaccine treated patients, 3.4 years in historical contols, P value of 0.02).Citation52 In 2011, Rӧllig et al. reported results of a phase II trial evaluating an idiotype pulsed dendritic cell vaccine, in conjunction with keyhole limpet hemocyanin(KLH) in patients with early stage myeloma. 9 patients with Stage-I myeloma were treated with 5 doses of vaccine administered at 4 weekly intervals. Responses were variable with Id-specific T cell proliferation was demonstrated in 5 out of 9 patients(56%) and a reduction in M protein was observable in only 3/9 patients treated.Citation53
Based on their observation that the cancer-associated protein NY-ESO-1 is highly expressed in poor-prognosis myeloma and is highly immunogenic,Citation54,55 Van Rhee et al are conducting a phase II/III clinical trial vaccinating myeloma patients, post autologous transplantation, with peptide vaccine comprising MAGE-A3 or NY-ESO-1 peptide and GM-CSF adjuvant.
Westermann et al. investigated the use of infusions of non-primed, ex-vivo generated dendritic cells in the treatment of chronic myeloid leukemia(CML).Citation56 In their phase I/II study, 10 patients with chronic phase bcr/abl+ CML, not in adequate cytogenetic response after conventional therapy, were given of 4 subcutaneous injections of increasing numbers of autologous dendritic cells on days 1, 2, 8 and 21. Their vaccination was well tolerated and 4 of 10 patients improved their cytogenetic/molecular responses, while all patients demonstrated improved T cell proliferative capacity following ex vivo stimulation, after vaccination. Cathcart et al. conducted a phase II trial whereby 14 patients with chronic phase bcr/abl+ CML were vaccinated 5 times, on days 0, 7, 21, 35, and 54 with a bcr/abl derived fusion peptide mixed with Quillaja saponaria, an immune adjuvant. 11 of 14 patients had increased CD4 derived IFN-gamma release after vaccination, with just 3 patients showing transient improvements in their cytogenetic response, as shown by PCR.Citation57 Currently, no studies have been published on vaccination with dendritic cell: peptide fusion products in leukemia, but these 2 studies demonstrate the clear potential for a dendritic cell based vaccine in CML, using the bcr/abl fusion peptide as the tumor associated antigen.
An alternative approach to introducing primed or naïve dendritic cells to patients is vaccination with a protein or peptide capable of recruiting and stimulating native dendritic cells. Several groups have conducted feasibility and phase I/II trials of peptide vaccination with peptides derived from the leukemia associated antigen WT1, in combination with immune adjuvants.Citation58,59 Oka et al vaccinated 14 patients with AML with WT1 peptide emulsified with Montanide ISA51 adjuvant at 2 weekly intervals. 9 of the 13 evaluable patients with leukemia demonstrated immunological response as defined by a 1.5x increase in WT1-specific CTLs determined by tetramer assay. Moreover, this correlated strongly with clinical responses, defined as either a reduction in blast count or WT1 expression.
Vaccines using DNA/RNA encoding tumor associated antigen
In 2013, Hobo et al. reported their phase I trial whereby 12 patients with stage I or II myeloma, in at least partial remission after autologous SCT, were treated with dendritic cell vaccines primed with KLH and electroporated with MAGE3, Survivin or B-cell maturation antigen(BCMA) mRNA. Vaccination was well tolerated with limited toxicity and they found antigen specific T cells in 3 of their 12 patients after vaccination, although M protein levels remained unchanged.Citation60
Van Tendeloo et al vaccinated 10 patients with AML with WT1 mRNA-electroporated dendritic cells, with an expansion in WT1 specific T cells demonstrated and correlating with 2 patients in partial remission, who were converted into sustained complete remission.Citation61 Van Driessche et al. have reported their phase I/II studies of a dendritic cell vaccine made by introducing mRNA encoding the Wilm's tumor(WT1) antigen to mature dendritic cells. 10 patients with AML in at least partial remission, were treated with 4 bi-weekly vaccinations. Their vaccination was well tolerated and 2 patients who were in partial remission after chemotherapy were converted into complete remission after vaccination, and this was associated with increases in WT1-specific CD8+ T cell frequencies, as demonstrated by tetramer staining.Citation62
Vaccines using apoptotic bodies derived from tumor cells
A recent area of interest has been the priming of dendritic cells with tumor associated antigen, in the form of apoptotic bodies. It has been postulated that apoptotic bodies allow uptake and processing of a larger quantity of antigen, compared to dendritic cell pinocytic vesicles taking up tumor lysate or in vitro transcription of transfected RNA. In one phase I study in CLL, the immune stimulatory molecule CD80 was expressed on a slightly higher percentage of Apo-DC in comparison to DC loaded with tumor lysate.Citation43 In a phase I study in CLL, Palma et al. vaccinated 15 patients with asymptomatic CLL with a vaccine product made by priming dendritic cells with apoptotic bodies of autologous CLL cells. The vaccine was given alone(Cohort I), or in combination with subcutaneous GM-CSF(Cohort II) or with IV low dose cyclophosphamide(Cohort III). There were no clinical responses, however 10/15 patients were designated ‘immune responders’, as defined by higher levels of IL-2, IL5, IFN and a positive anti-leukemic ex-vivo T cell proliferation assay. The strongest responses were seen in the cohort given cyclophosphamide, although the study was not powered to demonstrate superiority.Citation35
A similar approach to priming dendritic cells was investigated in the setting of acute myeloid leukemia. Kitawaki et al. treated four AML patients(with <20% blasts on bone marrow biopsy after standard of care chemotherapy), with 5 doses of a vaccine generated by pulsing dendritic cells with autologous apoptotic blasts, alongside KLH. Two of the 4 treated patients showed immune responses as determined by raised IFN levels, and the one HLA-A*2402-positive patient was shown to have had induction of CD8+T-cell responses to WT1- and human telomerase reverse transcriptase, indicating success of the dendritic cell pulsing. The two ‘responder’ patients appeared to have longer disease free remissions.Citation63
Whole tumor cell vaccines
Priming DCs with the whole tumor cell can be achieved with a lysed or intact tumor cell. In their phase I clinical trial, Hus et al vaccinated patients with early-stage B-cell chronic lymphocytic leukemia, with HLA matched allogeneic DCs primed with tumor lysate.Citation24 In their subsequent study, they switched to autologous DCs. In total, 12 patients were vaccinated up to 8 times over at bi-weekly intervals, and this was well tolerate with minor skin reactions seen at the vaccine site. An increase in CD8+ T cells specific to the leukemia-associated antigens RHAMM or fibromodulin was detected in 4 patients. A clinical response, as defined by a decrease in leukocytosis and CD19+/CD5+ leukemic cells was seen in 5 patients, and 3 patients showed a stable disease.Citation64
In 2009, DiNicola et al reported their trial in which 18 relapsed patients with an indolent non Hodgkin's lymphoma were treated with dendritic cells primed with whole, heat shocked and irradiated autologous tumor cells. Three patients showed continuous complete responses(CRs) and 3 partial responses(PRs) at 50.5 months and this was significantly associated with a reduction of circulating regulatory T cells(TRegs) and increase in natural killer(NK) cells. Additionally, in some patients, vaccination significantly boosted the IFN-gamma-producing T-cell response to autologous tumor challenge.Citation65
Our group has developed a whole cell vaccine whereby patient derived tumor cells are fused to ex-vivo generated autologous dendritic cells. In a phase I dose escalation study in myeloma,Citation39 17 patients with multiple myeloma(median of 4 prior regimens) underwent vaccination with DC/MM fusions in conjunction with 4 days of GM-CSF administered at the vaccine site. Vaccine production was successful in all patients and was well tolerated without evidence of clinically significant autoimmunity. Vaccination resulted in a mean 10 fold expansion of CD4 and CD8 myeloma specific T cells as determined by the percentage of cells expressing IFNg in response to ex vivo exposure to autologous tumor lysate. Similarly, vaccination resulted in the development of myeloma specific antibody responses. Prolonged disease stabilization was seen in a subset of patients. In a subsequent phase II trial, vaccination with DC/MM fusion cells was administered in conjunction with autologous stem cell transplantation(ASCT). The period of post-transplant lymphopoietic reconstitution was associated with the expansion of myeloma specific T cells that was further boosted following vaccination. Seventy-eight percent of patients achieved a CR or VGPR(47% CR/nCR; 31% VGPR). Thirty-one percent achieved a CR/nCR in the early post-transplant period, whereas an additional 17%(6 patients: 4 from VGPR, 2 from PR) achieved CR/nCR as best response only after day 100 post-transplant and after undergoing vaccination. The presence of late responses several months after ASCT is consistent with an impact of vaccine therapy on post-transplant residual disease.Citation48
In acute leukemia, we are conducting a clinical trial in which AML patients who are in a first or second complete remission following chemotherapy are given 3 monthly doses of DC/AML fusion cells. Interim results from 13 evaluable patients(who have received at least 2 vaccinations) reveal 9 patients(69%) in sustained remission at 28 months.Citation66
A novel approach to augment antigen presenting activity in patients with cancer has been to vaccinate them with irradiated autologous tumor cells engineered to secrete GM-CSF. It is thought that paracrine production of GM-CSF can stimulate the recruitment, maturation, and function of dendritic cells in vivo,Citation67,68 overcoming the described qualitative and quantitative deficiencies of antigen presenting cells in cancer patients. Ho et al conducted a Phase I clinical trial whereby high-risk acute myeloid leukemia or patients with MDS were immunized with autologous, irradiated, GM-CSF-secreting tumor cells early after allogeneic, nonmyeloablative HSCT.Citation67 The immunization was broadly well tolerated with one patient suffering a GVHD type skin reaction. Six long-term responders showed marked decreases in the levels of soluble NKG2D ligands, indicative of NK cell tumor specific activity, and 3 demonstrated normalization of cytotoxic lymphocyte NKG2D expression as a function of treatment.
Leukemia derived dendritic cells
One approach in overcoming quantitative and qualitative defects in dendritic cells is to generate mature dendritic cells from immature myeloid cells. In CMLCitation69,70 and AML,Citation71-73 dendritic cells can be generated from ex-vivo leukemia blasts themselves, which has the added advantage of negating the need to load tumor-associated antigen, while expressing these antigens in the context of the necessary co-stimulatory signals. Leukemia blast derived cell linesCitation74 that have been stimulated to differentiate into dendritic like cells with antigen presenting capabilities. The advantage of this technique is the cells potential to induce an immune response against the whole repertoire of leukemic antigens without the need for exogenous loading. However there are concerns over the re-infusion of leukemic dendritic cells that have been purported to be a component of tumor related immune escape.Citation75
Litzow et al subcutaneously vaccinated 6 CML patients with ex vivo leukemic derived dendritic cells, 4 of whom were also on Imatinib therapy. While they observed no clinical responses, there were increased circulating CML specific T cells following therapy.Citation76 Roddie et al vaccinated 5 AML patients in complete remission with 4 escalating doses of dendritic cell like leukemia cells. One patient developed an eczematous rash and auto-antibodies suggestive of the induction of auto-immunity. Immunological response, as demonstrated by increased INF-g production by leukemia specific T cells was demonstrated in 4 patients, although only 2 of the 5 remained in remission more than one year post vaccination.Citation77
A practical draw-back of this approach is that Leukemia derived DCs can only be generated from a minority of patients, as FLT-ITD mutations or a lack of CD14 expressed on blasts prevent the maturation to the DC phenotype.Citation78,79
Enhancing response to vaccination
A critical factor to consider in designing clinical trials evaluating dendritic cell vaccines is the immunologic milieu into which the vaccine is being administered. Tumor induced immune suppression may blunt immune response to vaccination in patients with advanced disease. Factors contributing to tumor induced immune suppression include an increased presence of regulatory T cells,Citation80 increased circulating myeloid derived suppressor cells(10) and skew of polarity of dendritic cells toward a tolerogenic phenotype.Citation81 Additionally, a variety of soluble factors such as indolamine, VEGF, TGFB and IL-10 inhibit both effector T cell function and dendritic cell maturation.Citation82 Moving forward, ongoing and future studies that incorporate vaccination in minimal disease states, following chemotherapy and following transplantation, hold promise as a means of eradicating minimal residual disease and preventing relapse. We have identified the post allograft setting as an optimal time for immunotherapy as during lymphopoietic reconstitution there is a relative depletion of immune suppressive regulatory T cells which would otherwise limit the response to vaccination.Citation83
A second approach toward enhancing response to vaccination is combining vaccination with stimulatory cytokines, immune-modulatory drugs, and immune checkpoint blockade.
While pre-clinical studies have used immune stimulating cytokines such as IL-2 in combination with various immune therapiesCitation84 in an attempt to enhance immune responses, clinical trials using dendritic cells augmented to secrete have been limited to the use of GM-CSF. In the setting of AML, Borello et.al conducted a phase II trial where 28 patients were given induction chemotherapy, followed by a single immunotherapy treatment of allogeneic immortalized K562 tumor cells that had been modified to secrete high levels of GM-CSF.Citation85 Patients primed lymphocytes were collected by plasmapheresis and then underwent autologous stem cell transplantation, receiving the primed lymphocytes at day 0, followed by 8 further immunotherapy treatments over a 6 month period. Treatment with the immunotherapy lead to a decrease in WT1 transcripts in 69% of patients after their first immune therapy, and increase in CD4+ derived IFN-gamma and granzyme. The immune therapy lead to an overall survival of 73.4% vs. 57.4% for patients who were ineligible for the immunotherapy. Of note, only 6 patients had detectable levels of GM-CSF at any one time point and importantly, the study was not designed to demonstrate the superiority of GMCSF modified K562 cells over wildtype.
Lenalidomide is a second-generation thalidomide analog used in the treatment of myeloma. Lenalidomide has potent immunomodulatory functions which have not been fully elucidated but are thought to enhance activation of T and NK cells. In addition, in a preclinical study the immunomoulatory agents Lenaliomide and Pomalidomide have been shown to have an effect on dendritic cells themselves, with increased expression of CD86 on DCs, and increased uptake of fluorescent beads, signifying increased antigen presentation.Citation86 In preclinical studies, Lenalidomide enhanced immune response to vaccination,Citation87 and a clinical trial combining Lenalidomide with vaccination is planned.
The PD1/PDL1 pathway serves as a negative checkpoint for T cell activation and CTL-mediated targeting of tumor cells. In patients with cancer, up-regulated expression of PD-1 on T cell binds PDL-1 on tumor cell, resulting in the suppression of T cell capacity to secrete stimulatory cytokines.Citation11,83 Following autologous transplantation for myeloma, T-cell expression of PD-1 was observed to return to normal levels. In our ex-vivo study, the effect of PD-1 blockade on T-cell response to DC/whole tumor fusions was investigated. The presence the anti-PD1 antibody CT-011, promoted the vaccine-induced T-cell polarization toward an activated Th1 phenotype from a Th2 cytokine profile. Interestingly, a concomitant decrease in regulatory T cells and enhanced killing in a cytotoxicity assay was observed. A clinical trial combining PDL1 blockade with DC/tumor fusion cell vaccination for patients with AML, is underway.Citation83
Conclusion
The potency of the immune system in controlling hematologic malignancies is highlighted in the allogeneic transplant setting. However, the lack of specificity of allo-reactive T cells results in graft vs. host disease. The design of dendritic cell vaccines as a means of eliciting tumor specific immune responses has the potential to result in durable responses with minimal toxicity. A major focus of research interest lies on developing strategies to broadly target the malignant clone, mitigating the potential for immune escape, while minimizing the risk of the induction of autoimmunity. Importantly, immunotherapeutic strategies that target tumor initiating cell populations have the potential to eradicate the source of disease recurrence and chemotherapy resistance.
While most studies have focused on patients with refractory disease, immunotherapeutic approaches will likely be most effective in patients with low tumor burden. Studies evaluating the combination of dendritic cell vaccines with chemotherapy, immunomodulatory drugs, and immune checkpoint inhibitors, are ongoing.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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