|Year : 2018 | Volume
| Issue : 3 | Page : 905-910
Sabry A Shoieb1, Mohammad A Abdelhafez1, Alaa E Abdelhamid1, Amira M Elmasry2
1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Hemodialysis Unit, Almahalla Alkobra Fever Hospital, Almahalla Alkobra, Egypt
|Date of Submission||06-Jan-2017|
|Date of Acceptance||11-Mar-2017|
|Date of Web Publication||31-Dec-2018|
Amira M Elmasry
Almahalla Alkobra City, Elgharbia Governorate
Source of Support: None, Conflict of Interest: None
The objective of this study was to review the role of immunotherapy in treating multiple myeloma (MM). Medline databases (PubMed, Medscape, and ScienceDirect) and all related materials available on the internet from January 1993 to December 2016 were searched. The initial search presented 90 articles of which 29 met inclusion criteria. The articles studied the role of immunotherapy in treating MM. If the studies did not fulfi ll inclusion criteria, they were excluded. Study quality assessment included whether ethics approval was gained, eligibility criteria were specifi ed, appropriate controls were used, adequate information was provided, and whether defi ned assessment measures were undertaken. Each study was reviewed independently; the data obtained were rebuilt into a new language according to the need of the researcher and arranged into different topics through the article. All articles included in this review were human studies. The studies defi ne myeloma as a disorder of differentiated plasma cells. Understanding immune dysregulation in myeloma has led to development of new therapies. Immunotherapy is a promising treatment modality in the management of MM. Many novel immunotherapies such as immunomodulatory drugs, adoptive cell therapy, and monoclonal antibodies were reviewed. Basic research efforts toward better understanding of normal and missing immune surveillance in myeloma have led to development of new strategies and therapies that require the engagement of the immune system. Many novel immunotherapy strategies such as immunomodulatory drugs, adoptive cell therapy, and monoclonal antibodies are currently under investigation in clinical trials.
Keywords: adoptive cell therapy, chimeric antigen receptor T cells, immunotherapy, monoclonal antibodies, myeloma, vaccines
|How to cite this article:|
Shoieb SA, Abdelhafez MA, Abdelhamid AE, Elmasry AM. Myeloma immunotherapy. Menoufia Med J 2018;31:905-10
| Background|| |
Multiple myeloma (MM) is a plasma cell neoplastic disease that often runs an aggressive and incurable course. It accounts for about 10% of hematologic malignancies, and carries an annual incidence of up to 5.6/100 000 persons in the western hemisphere. The hallmark feature of MM is monoclonal expansion of plasma cells in the bone marrow with accompanying excessive production of monoclonal immunoglobulins that produce an ‘M spike’ on serum protein electrophoresis. Indeed, MM has been described as an evolving spectrum with isolated monoclonal antibody (mAb) overproduction, an essentially benign condition referred to as monoclonal gammopathy of undetermined significance (MGUS) at one end and symptomatic extramedullary MM at the other end. In between both ends lies what is often referred to as asymptomatic (or smoldering) myeloma, which is characterized by clonal expansion of plasma cells in the bone marrow in addition to excessive mAb production but without the classic syndrome of symptomatic myeloma that is often described by the acronym CRAB (elevated calcium, renal insufficiency, anemia, and bone disease).
Recent advances in the understanding of MM's pathophysiology and the arrival of novel therapeutic agents have revolutionized the management of this disease and dramatically improved survival in the last two decades. Indeed, median survival increased from about 2 years in the 1980s up to 5 years in 50% of patients treated today (and even up to 10 years or longer in about 20%). Nevertheless, MM still remains an incurable disease, and therefore the quest for more efficient myeloma therapy and induction of meaningful response persists.
A better understanding of the immune evasion by myeloma cells and the role of interactions between tumor cells and other elements in the bone marrow microenvironment have inspired many ongoing studies targeting the immunological pathways implicated in myeloma growth and survival. Immunotherapy bears significant promise in myeloma treatment, and in this review we will examine various immunotherapeutic approaches currently being used or evaluated in the management of MM.
| Materials and Methods|| |
We reviewed articles on the role of immunotherapy in the treatment of myeloma from Medline databases (PubMed, Medscape, ScienceDirect) and also other materials available on the internet – for example, PubMed, Medscape, and ScienceDirect. We used ‘immunotherapy/MM’ as search terms. In addition, we examined references from specialist databases, reference lists in relevant publications, and published reports. The search was performed in electronic databases for data from January 1993 to December 2016.
All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria:
- Human studies
- Published in English language
- Published in peer-reviewed journals
- Focused on the role of immunotherapy in the treatment of MM
- Discussed immune dysregulation in the pathogenesis of MM.
If the studies did not fulfill the above-mentioned criteria, they were excluded, such as reports without peer-review and studies not focused myeloma immunotherapy.
The analyzed publications were evaluated according to evidence-based medicine criteria using the classification of the US Preventive Services Task Force:
- Level I: evidence obtained from at least one properly designed, randomized controlled trial
- Level II-1: evidence obtained from well-designed controlled trials without randomization
- Level II-2: evidence obtained from well-designed cohort or case–control analytical studies, preferably from more than one center or research group
- Level II-3: evidence obtained from multiple, time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
- Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
The quality of all the studies was assessed. Important factors included study design, attainment of ethics approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for, and appropriate data analysis would be carried out in addition to an explanation of missing data.
Each study was reviewed independently. The data obtained were rebuilt in new language according to the need of the researcher and arranged according to topics through the article.
| Results|| |
Study selection and characteristics
In total, 90 potentially relevant publications were identified. Sixty articles were excluded as they did not meet our inclusion criteria. A total of 30 studies were included in our review as they were deemed eligible by fulfilling inclusion criteria. All articles included in this review were human studies. The majority of studies discussed the role of immunotherapy in the treatment of myeloma. The studies were analyzed with respect to study design using the classification of the US Preventive Services Task Force.
Immune dysregulation in multiple myeloma
It is well established today that all MM patients have a pre-existing nonmalignant stage known as MGUS. The mechanism of progression is not solely limited to genetic mutations in the plasma cells but to alterations in the marrow microenvironment and more importantly to loss of immune surveillance. Although myeloma is primarily a disorder of the B-cell lineage, the T-cell compartment is frequently affected. This defect is characterized by a significant reduction in the absolute number of CD4 cells, whereas the numbers of CD8 lymphocytes remain normal, leading to a decreased CD4/CD8 ratio. In fact, loss of tumor-specific T cells of CD4, CD8, and natural killer T-cell (NK-T) subsets is a hallmark for progression from MGUS to MM. The balance between regulatory T cells (Treg) and T helper (Th) 17 cells is essential for maintaining antitumor immunity in MM.
Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against infections and tumor cells. In MM patients, Tregs seem to contribute to myeloma-related immune dysfunction. Th17 cells protect against fungal and parasitic infections and participate in inflammatory reactions and autoimmunity. The interplay of transforming growth factor-β and interleukins-6 (IL-6), expressed at high levels in the bone marrow of myeloma patients, may affect generation of Th17 cells both directly or through engagement of other proinflammatory cytokines, and thereby modulate antitumor immune responses. The balance between Tregs and Th17 cells seems to be skewed toward Th17 cells. This has been affected by IL-6, tipping the balance between reciprocal developmental pathways of Tregs and Th17s toward the Th17 route. The result is significant immune deficiency in MM.
MM immune dysregulation affects other aspects of the immune system as well, directly affecting antigen presentation and upregulation of inhibitory antigens that promote immune escape and growth advantage for malignant clones. On the antigen-presenting side, elaborate studies on different aspects of dendritic cell (DC) biology have revealed somewhat conflicting results. Some studies have reported defects in peripheral blood DCs such as decreased numbers of circulating peripheral blood monocytes and myeloid DCs. Other studies have shown phenotypically and functionally quasinormal DC biology from the peripheral blood and marrow of MM patients, and have suggested a contributory role of tumor microenvironment to the previously described defects. This was suggested by elevated IL-6 and vascular endothelial growth factor levels in the bone marrow sera in MM patients, which led to an inhibition of induction and maturation of DCs.
Immunotherapy in multiple myeloma
Immunomodulatory drugs (IMiDs) is a class of drugs that directly affect MM cells and bone marrow microenvironment, leading to modulation of cytokines, inhibition of angiogenesis, and augmentation of immune effector numbers and function (T-cell, NK-cell, and NK-T). Recently, interaction of IMiDs with cereblon, a ubiquitin ligase component responsible for substrate binding, was shown to be crucial for direct cytotoxic and immune-related effects. Lenalidomide and pomalidomide also inhibit Treg proliferation. In addition to their effects on T cells, IMIDs were shown to augment NK-cell antibody-dependent cellular cytotoxicity (ADCC) by increasing NK cells.
Two separate vaccination approaches have been developed. The first approach is peptide-based vaccines. The pioneer of these approaches, use of idiotype proteins, an attractive concept as it is, did not meet expectations as potential targets possibly secondary to the poor immunogenical nature of the protein as well as low expression of these proteins on the plasma cell surface. There have been efforts to increase immunogenicity through the use of keyhole limpet hemocyanin, granulocyte macrophage colony stimulating factor, tetanus toxoid fragments, and DCs.
On the other hand, subsequent identification of tumor-associated antigens and their use as targets was able to generate cellular responses when used individually and/or in combination in preclinical studies. Clinically, initial results using a single peptide-based vaccine demonstrated that such vaccines can be used with a few adverse effects and can elicit immune responses but with modest effect on disease control. In particular, there is a focus on cocktail of fragments of peptides that have abundant expression on myeloma cells.
The second vaccination approach involved DC/myeloma cell fusion (DC/MM). This strategy took advantage of the ability of the DC to present several antigens from the cell to the host.
The development of effective cytotoxic mAbs therapies in MM has been hindered by the lack of distinctively and constitutively expressed target molecules on malignant plasma cells. Studies early after the turn of the millennium have demonstrated only minimal activity of anti-CD20 rituximab, which was expressed on 20% of plasma cells. This was followed by several mAbs. We focused on two mAbs that demonstrated promising clinical results in MM.
Elotuzumab (anti-CD319 antibody): CD319 is a transmembrane glycoprotein expressed on normal and malignant plasma cell membranes as well as on NK cells. An immunoglobulin G (IgG) antibody-targeting CD319, elotuzumab, has shown impressive in-vitro activity against myeloma cells, killing myeloma cells through ADCC, although using the same receptor for activation of NK cells. This antibody did not have complement-dependent cytotoxicity.
Daratumumab (anti-CD38 antibody): CD38 is a type II transmembrane glycoprotein with multiple proposed functions in cell adhesion, signaling, and enzymatic (cellular nucleic acid metabolism) activity, and is expressed on multiple hematopoietic and nonhematopoietic cell types. Among the many hematopoietic cells that harbor this antigen are medullary thymocytes, subpopulations of both activated B and T lymphocytes, NK cells, and DCs. Daratumumab is a fully human IgG1κ mAb directed against CD38, which has shown activity against myeloma cells in preclinical models. Among the proposed mechanisms of action of daratumumab, in addition to well-described complement-dependent cytotoxicity and ADCC, are antibody-dependent phagocytosis, induction of autophagy/apoptosis, as well as loss of enzymatic activity.
Several new mAbs are under development for various cell member targets and others are in early stages, but a few are worth mentioning. The first is B-cell maturation antigen, a protein of tumor necrosis factor receptor superfamily, which is crucial for long-term survival of plasma cells through its binding B-cell activating factor and proliferation-inducing ligand (APRIL). Several studies assessing mAb against B-cell maturation antigen and antibody drug conjugates are underway. Antibodies against CD138 (syndecan) seem to be limited by the soluble forms of CD138; however, when a mAb was combined with tubulin polymerization inhibitor maytansinoids, there were significant preclinical as well as early clinical activities in the phase I trial. Antibodies targeting CD56 and CD74 are in the early stages of clinical development.
Immune checkpoint inhibitors
Immune checkpoint inhibitors targeting programmed death-1 (PD-1) (pidilizumab, pembrolizumab, and nivolumab) on T cells or its cognate PD-ligand-1 (PD-L1) on tumor cells have established activities in many different types of cancers. Although the initial postulated mechanism of action of the checkpoint blockade was primarily through the engagement of T cells that are regulated by peripheral tolerance, a growing body of evidence has suggested important roles of antigen-presenting cells and activation of NK cells.
At present, there are several clinical studies investigating the use of immune checkpoint inhibitors in various combinations in MM – the majority being PD-1 trials. In addition, there is a growing interest in its cognate molecule, PD-L1, as this is a part of the signaling pathway that is harbored on the tumor itself and at least in theory has the additional potential for ADCC. This ligand is shown to be expressed on malignant plasma cells. In addition, PD-L is also expressed on other cells as well, such as on plasmacytoid DCs and myeloid-derived suppressor cells, both of which play a role in the immunosuppressive state in myeloma. The use of PD-L1 antagonists is also being explored in the context of the presence or absence of IMiD.
Adoptive T-cell therapies
Early studies suggest that early lymphocyte count recovery after auto-stem cell transplantation correlated with improved disease control. Several trials involved ex-vivo co-stimulation of autologous T cells through immunomagnetic beads, which in the presence of IL-2 led to significant activation and expansion of T cells. Infusion of these cells after myeloablative bone marrow conditioning and autologous stem cell transplantation led to early lymphocytosis. In trials using peripheral blood, there was no clear evidence for a tumor-specific T-cell enhancement effect and no impact on outcome. This was probably related to nonspecific stimulation of the entire T-cell repertoire including Treg cells.
Chimeric antigen receptor T cells
Single chimeric antigen receptor T-cell-based therapy (CART) represents a huge leap in immunetherapy. CART cells, constructed by fusing the single-chain variable fragment (scFv) of a mAb specific for a surface antigen with an intracellular signaling domain, have shown activity in several CD-19-related diseases. The major histocompatibility complex-independent tumor recognition, in-vivo expansion, and memory cell generation confer these cells a clear advantage over naked antibodies or adoptively transferred tumor-reactive T cells. A successful example of CD19-targeted CART-cell approach was recently published, suggesting activity of this therapy.
T-cell receptor transgenic T cells
Infusion of autoengineered T cells with affinity-enhanced TCR specific for a common peptide shared between two cancer testis antigens (NY-ESO-1 and LAGE-1) in MM was recently reported. However, as these cells are human leukocyte antigen dependent, this approach had limited utility compared with CART cells.
IL-6 is a cytokine that has been under spotlight in myeloma since the late 80 s as a driver for myeloma, which has raised the question of benefit of targeting this cytokine for therapeutic purposes.
IL-15 is a cytokine that has a critical role in CD8 memory cell and NK-cell development, proliferation, and activation, making it an attractive target. A complex with superagonistic activity against this cytokine, ALT-803, was recently developed, which in preclinical models was able to use specifically CD8 memory cells. However, NK cells were also activated, and the antimyeloma activity was independent of this activation.
| Discussion|| |
The success of any antigen-specific immunotherapeutic strategy depends critically on the choice of target antigen. In the case of idiotypic proteins, a study that investigated the benefit of using idiotype pulsed DCs generated from CD34 progenitors showed good tolerability and safety in 11 patients, yet poor biological response was seen in about half, some with increase in humoral response and even less with T-cell activity.
DC/MM fusions have been evaluated in phase I/II clinical trials. In both studies vaccination with DC/MM fusions were well tolerated and stimulated tumor-specific immunity as evidenced by expansion of tumor-reactive CD4 and CD8 T cells and induction of tumor-specific antibody responses. In the second trial, infusion of DC/MM cells on day 100 after transplant was associated with depletion of Treg cells. Interestingly, a quarter of patients with partial response converted to complete response after vaccination, suggesting that vaccine-induced immune responses eliminated minimal residual disease.
A large phase III study involving 600 relapsed MM patients confirmed the efficacy of the combination of elotuzumab plus lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone; progression-free survival (PFS) was 68 and 41% at 1 and 2 years (compared with 57 and 27% in controls). Interestingly, elotuzumab also showed activity against this disease with high-risk cytogenetic features such as t(4;14) and del(17p).
In a phase I/II study, recently published by Lokhorst et al., impressive clinical responses were seen in the heavily pretreated patient population, with 64% being double refractory to PIs and IMiDs and 76% had undergone auto-stem cell transplantation. Daratumumab as a single agent yielded 36% overall response rate in the 16 mg/kg arm, and remarkably, in the responder group, 65% remained progression free at 12 months.
A phase I study with nivolumab reported disappointing results with no objective responses in 27 myeloma patients; however, 67% of patients remained in stable in a population where two-thirds of MM patients were heavily pretreated with more than three lines of treatment.
Another PD-1 antibody, pidilizumab, was investigated through a phase I trial, which enrolled 17 patients with various hematological malignancies and showed stable disease in the single myeloma patient in the cohort, but with a durable response for more than 13 months.
A total of 24 patients (MM cells expressed NY-ESO-1 and/or LAGE-1) were treated, and at last follow up eight remained in remission with a median PFS of 19.1 months and a median overall survival of 32 months. The duration of response was reasonable and seems to be better than that expected in this population. Initial laboratory data suggested that the infused cells remain functional in the absence of IL-2 and without exhaustion for up to 1 year. Relapse patients were both antigen negative (indicating mutational change in the target) and positive (probably reflecting T-cell exhaustion). However, this approach had a limited utility compared with CART cells.
A phase I/II dose escalation study with chimeric monoclonal anti-IL-6 antibody resulted in a reduction of endogeneous production, an effect that was attributed to the blockage of a positive feedback loop.
A phase II randomized, double-blind, placebo-controlled study was carried out where another anti-IL-6 antibody, siltuximab, in combination with bortezomib, was compared with the bortezomib and placebo combination. In this study, addition of siltuximab to bortezomib in relapsed/refractory MM failed to improve PFS or overall survival.
| Conclusion|| |
MM is a disorder of differentiated plasma cells. Despite advances in myeloma treatment, it remains an incurable disease. Immunotherapy is a promising treatment modality to circumvent challenges in the management of MM. Obstacles in the way of developing an ideal immunotherapy for MM are primarily the heterogeneity of the disease and difficulties in identifying an ‘ideal target’ that is expressed exclusively by the malignant cells. As malignant plasma cells are shielded by a tumor microenvironment that supports their aggressive growth, targeting this environment also seems a reasonable approach. Many novel immunotherapy strategies such as IMiDs, adoptive cell therapy, and mAbs are currently under investigation in clinical trials. It is important to note that most therapies have shown clinical efficacy and may be valuable tools for the management of all stages of MM in the future.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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