Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

Kwiatkowska-Borowczyk, Eliza; Czerwińska, Patrycja; Mackiewicz, Jacek; Gryska, Katarzyna; Kazimierczak, Urszula; Tomela, Katarzyna; Przybyla, Anna; Kozłowska, Anna; Galus, Łukasz; Kwinta, Łukasz; Dondajewska, Ewelina; Gąbka-Buszek, Agnieszka; Żakowska, Monika; Maćkiewicz, Andrzej

doi:10.1080/2162402x.2018.1509821

Cited by 16 publications

(19 citation statements)

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“…H6 serves as a molecular adjuvant for AGI-101H and is secreted at the CD8+ and CD4+ T cell responses, blocks FoxP3 expression in CD25+CD4+ cells, inhibits the formation of regulatory T cells (Tregs), and induces dendritic cells (DC) maturation and cryptic antigen presentation [9], as well as the production of GM-CSF [10]. Downstream, H6 affects the activation of memory CD8+ and CD4+ T cells and natural killer (NK) cells and the inhibition of myeloid-derived suppressor cells (MDSCs) (data not published) [11]. Moreover, due to the expression of the gp130 receptor on the cells composing the vaccine, chronic autocrine exposure to H6 leads to activation of the JAK1/STAT3-P/Oct4 pathway, which changes the phenotype of these cells towards a melanoma stem cell-like phenotype [11,12].…”

Section: Introductionmentioning

confidence: 99%

Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model

Gąbka-Buszek

Kwiatkowska-Borowczyk

Jankowski

et al. 2020

Vaccines

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Therapeutic cancer vaccines have elicited renewed interest due to the development of immune checkpoint inhibitors. The role of these vaccines is to induce specific effector cells for killing cancer cells. Cancer stem cells (CSCs) are responsible for tumor growth and progression. Accordingly, they are targets for various cancer therapies, including immunotherapy. Here, we demonstrate the effectiveness of melanoma vaccines composed of genetically modified tumor cells admixed with melanoma stem-like cells (MSC) or induced pluripotent stem cells (iPSCs). Two vaccines were constructed. The first vaccine contained cells derived from B16F10 melanospheres (SFs) with CSC characteristics. The second vaccine contained syngeneic murine induced pluripotent stem cells (miPSCs). iPSCs or SF cells were admixed with B16F10 cells, modified with the designer cytokine Hyper-IL6(H6) (B16/H6). Control mice received B16/H6 cells, B16F10 cells or PBS. Immunization with either vaccine significantly inhibited tumor growth and increased disease-free survival (DFS) and overall survival (OS) in C57BL/6 mice. Mice treated with the SF or iPSC vaccine demonstrated increased activation of the immune response in the vaccination site and tumor microenvironment compared to those treated with B16/H6, B16F10 or PBS. Higher infiltration of dendritic cells (DCs) monocytes, and natural killer (NK) cells; lower numbers of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs); higher levels of the cytokines INFγ and IL-12 were observed with the novel vaccines than with the control treatments. In vitro restimulation of splenocytes derived from mice immunized with B16F10 cell, SF cell or miPSC lysates increased the proliferation of CD4+ T helper lymphocytes and secretion of cytokines. An increased serum titer of antibodies directed against B16F10 cells was found in mice immunized with the SF vaccine. The most effective DFS and OS extensions were reached with the miPSCs vaccine. The described results form the basis for a novel platform for the next generation of cancer vaccines composed of allogeneic cancer-specific cells modified with a molecular adjuvant gene and admixed with allogeneic miPSCs or SFs.

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Section: Introductionmentioning

confidence: 99%

Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model

Gąbka-Buszek

Kwiatkowska-Borowczyk

Jankowski

et al. 2020

Vaccines

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“…We previously described a functionally active, ALDH1A1specific CD8+ T cell population in the periphery of vaccinated patients associated with AGI-101H treatment. 4 After each vaccine dose, the number of ALDH1A1-specific CTLs significantly increased and then returned to baseline levels by the next booster (1 month later). Moreover, AGI-101H immunization induced the generation of antibodies specific to ALDH1.…”

Section: Discussionmentioning

confidence: 90%

“…A subset was randomly selected for participation in the present study. Previously, we observed a significant induction of functionally active ALDH1A1specific CD8+ T cell population and up-regulation of specific anti-ALDH1A1 antibodies in vaccinated patients 4 ; however, neither the global effect of AGI-101H administration nor it's underlying mechanism have been fully characterized.…”

Section: Introductionmentioning

confidence: 86%

“…We developed therapeutic allogeneic whole cell melanoma vaccine (AGI-101H) that has been clinically tested since 1997 and enabled the long-term survival of a substantial fraction of immunized patients. [1][2][3][4][5] The AGI-101H vaccine is comprised of two melanoma cell lines retrovirallytransduced with a designer cytokine gene encoding a fusion protein of interleukin 6 (IL-6) linked with the soluble IL-6 receptor (sIL-6R), referred to as hyper-IL-6 or H6. [1][2][3][4][5] H6 modification led to the conversion of vaccine cells into melanoma stem cells (MSCs)-like with high activity of aldehyde dehydrogenase isoenzyme (ALDH1A1).…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic melanoma vaccine with cancer stem cell phenotype represses exhaustion and maintains antigen-specific T cell stemness by up-regulating BCL6

et al. 2020

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We developed a therapeutic, gene-modified, allogeneic melanoma vaccine (AGI-101H), which, upon genetic modification, acquired melanoma stem cell-like phenotype. Since its initial clinical trial in 1997, the vaccine has resulted in the long-term survival of a substantial fraction of immunized patients (up to 20 years). Here, we investigated the potential molecular mechanisms underlying the long-lasting effect of AGI-101H using transcriptome profiling of patients' peripheral T lymphocytes. Magnetically-separated T lymphocytes from AGI-101H-immunized long-term survivors, untreated melanoma patients, and healthy controls were subjected to transcriptome profiling using the microarray analyses. Data were analyzed with a multitude of bioinformatics tools (WebGestalt, DAVID, GSEA) and the results were validated with RT-qPCR. We found substantial differences in the transcriptomes of healthy controls and melanoma patients (both untreated and AGI-101H-vaccinated). AGI-101H immunization induced similar profiles of peripheral T cells as tumor residing in untreated patients. This suggests that whole stem cells immunization mobilizes analogous peripheral T cells to the natural adaptive anti-melanoma response. Moreover, AGI-101H treatment activated the TNF-α and TGF-β signaling pathways and dampened IL2-STAT5 signaling in T cells, which finally resulted in the significant up-regulation of a BCL6 transcriptional repressor, a known amplifier of the proliferative capacity of central memory T cells and mediator of a progenitor fate in antigen-specific T cells. In the present study, high levels of BCL6 transcripts negatively correlated with the expression of several exhaustion markers (CTLA4, KLRG1, PTGER2, IKZF2, TIGIT). Therefore, Bcl6 seems to promote a progenitor fate for cancer-experienced T cells from AGI-101H-vaccinated patients by repressing the exhaustion markers.

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“…Targeting malignancies through manipulating the immune system has seen success in a variety approaches ranging from whole cell vaccination, to autologous dendritic cell based vaccines and therapeutic immune-modulation [1][2][3][4][5]. But a number of opportunities and challenges remain.…”

Section: Introductionmentioning

confidence: 99%

Mimetic Vaccines in Immuno-Oncology

Pashov¹,

Kieber‐Emmons²

2019

Cancer Immunotherapy and Biological Cancer Treatments

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While the interest in cancer vaccines is renewed by some results in vaccinebased clinical trials, the premise still suffers from the incomplete concept of a successful vaccine. Future progress may come from matching preclinical data with clinical expectations while taking a step back to understand the systems perspective. A field that benefits most from this bird's eye view is tumor immunology. For instance, the accumulation over the last three decades of clear associations of T and B cell cross-reactivity between a set of host targets of autoimmunity and microbial antigens strongly supports a pathogenic role for molecular mimicry. Mimicry on its turn invites the concept of networks of molecular interactions. The intentional and rational approach to exploit mimicry in cancer vaccine development, while littered with failure, has provided also some insight into success. Here, we visit successes and underlying rationale to lend to future development of mimetic vaccines in immune-oncology.Keywords: vaccine, anti-idiotype, peptide, tumor associated carbohydrate antigens, carbohydrate mimetic peptide Cancer Immunotherapy and Biological Cancer Treatments 2 requires alternative immunotherapeutic strategies. One such strategy is to develop polyclonal humoral immune responses by active immunotherapy. Itself, this concept can have multiple approaches and an orchestra of potential mechanisms that encompass a dynamic systems immunology perspective (Figure 1). On the one hand the effect can be pursued by formulating a platform with multiple epitopes of target antigens [19]. On the other-making use of polyspecific (pan-antigen) mimetics to target simultaneously multiple antigens on cancer cells [17, 18]. A polyclonal antibody approach would target more than two antigens on a single tumor cell, which is expected to have even higher potential. This latter idea is a part of the conceptual evolution in immune-oncology harnessing polyclonal responses to cancer cells. Setting the stage: systems conceptsSystems immunology is now in focus to understand the immune system [20], especially in the context of vaccinology [21]. This perspective is ushering in a new era in vaccine development [22]. For the future, it is argued that successful approaches will depend on the elucidation of the entire network of immune signaling pathways that regulate immune responses with an eye toward integrating advances in computational and systems biology, genomics, immune monitoring, bioinformatics and machine learning [22,23].Systems immunology also teaches us that one antigen can substitute for another having the potential to regulate tolerance [24][25][26][27][28]. However, it is unclear why an immune system that is tolerant of its own self-antigens would respond to a self-antigen mimic in a vaccine. Antibodies referred to as anti-idiotypic are produced during

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Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

Cited by 16 publications

References 50 publications

Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model

Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model

Therapeutic melanoma vaccine with cancer stem cell phenotype represses exhaustion and maintains antigen-specific T cell stemness by up-regulating BCL6

Mimetic Vaccines in Immuno-Oncology

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