Journal of Clinical and Cellular Immunology
Open Access

Indoleamine 2,3-Dioxygenase (IDO); Silenced Dendritic Cell Vaccine with Ipilimumab in Treating Metastatic Melanoma Patients: A Case Report

Qing Chen¹, Wang Liu¹ and Zhongbin Zhoa^{1,2* *}Correspondence: Zhongbin Zhoa, Department of Medicine, Zhejiang University, Zhejiang, China, Email:

Author info »

Introduction

Metastatic melanoma is an aggressive form of skin cancer with limited treatment options and a high mortality rate. Immunotherapy, particularly immune checkpoint inhibitors, has emerged as a promising treatment strategy by harnessing the patient's immune system to recognize and attack cancer cells. This case highlights the use of combination therapy with ipilimumab, an anti-CTLA-4 monoclonal antibody, and an IDOsilenced dendritic cell vaccine in a patient with metastatic melanoma. The aim was to stimulate and diversify antitumour immune responses, potentially leading to improved outcomes [1].

Dendritic Cells (DCs) are the antigen-presenting cells that bridge the gap between innate and adaptive immunity [2]. DCs are being researched as vaccinations for cancer patients due to their powerful involvement in activating cytotoxic T cells. However, despite significant efforts to develop DC immunization as a cancer therapy, therapeutic effectiveness has been limited thus far. It has become clear that the presence of immune suppressive components in the immune system and tumor microenvironment is a major contributor to the dismal clinical outcomes [3].

The population of regulatory cells, which includes T-regulatory (Treg) cells, tolerogenic DCs and Myeloid-Derived Suppressor Cells (MDSCs), is one of the variables that contribute to immunosuppression. Treg and MDSC cells can connect with other cells like DCs to decrease their immune-activating activity. Tolerogenic DCs employ immunological inhibitory factors such as Interleukin-10 (IL-10), Indoleamine 2,3-Dioxygenase (IDO) and programmed death ligand-1 as one way. Immunosuppression caused by IL-10 is mediated via the impairment of DC maturation, T-cell and NK-cell activities [4,5]. IDO-positive DCs decrease T-cell responses and increase tolerance by depleting tryptophan and producing metabolic products, both of which can have an immunosuppressive impact. Furthermore, IDOpositive DCs drive T-cell development into Treg cells rather than clonal proliferation and effector cell differentiation [6].

Case Presentation

A 45-year-old male presented with metastatic melanoma, involving multiple lymph nodes and distant organs. The patient's disease had progressed despite previous treatments, including surgery, radiation therapy, and chemotherapy. Based on the patient's eligibility and informed consent, combination immunotherapy was initiated, consisting of ipilimumab and an IDO-silenced dendritic cell vaccine (Figure 1).

Figure 1: Vaccinating patient by using dendritic cell cancer therapy.

Results

Clinical response

Following the treatment initiation, the patient experienced a notable clinical response. Progressive reduction in the size of metastatic lesions was observed, both locally and at distant sites, as assessed by imaging studies. The patient also reported a significant improvement in overall well-being, including reduced pain and fatigue.

Immune monitoring

Immune monitoring was performed to assess the diversification and potency of the antitumour immune response. Peripheral blood samples were collected at baseline and after treatment initiation. Flow cytometry analysis revealed an increase in the frequencies of activated T cells, including CD8+ cytotoxic T cells and memory CD4+ T cells. Additionally, the patient demonstrated a substantial increase in the production of proinflammatory cytokines, such as Interferon-γ (IFN-γ) and Tumor Necrosis Factor-α (TNF-α).

Safety profile

Adverse events related to treatment were monitored closely. The patient experienced manageable immune-related adverse events, including skin rash, fatigue and mild gastrointestinal symptoms. These adverse events were effectively managed with supportive care and temporary discontinuation of treatment.

Discussion

The combination of ipilimumab and an IDO-silenced dendritic cell vaccine represents a rational approach to enhance antitumour immunity in metastatic melanoma. Ipilimumab blocks the CTLA-4 checkpoint, promoting T cell activation and proliferation. Concurrently, the IDO-silenced dendritic cell vaccine aims to overcome immunosuppression by targeting IDO, which is involved in the induction of immune tolerance [7].

The observed clinical response and immune monitoring results suggest the successful diversification and potentiation of the patient's antitumour immune response [8]. Increased frequencies of activated T cells and enhanced production of proinflammatory cytokines indicate the induction of a robust immune response against the melanoma cells.

The way that immunotherapies can diversify antitumor immunity is demonstrated by the activation of CD8+ T-cells against MART-1 and NY-ESO-1 in response to the vaccination and perhaps to ipilimumab [9]. Additionally, the production of a B-cell response against a number of putative melanoma antigens, some of which may be altered proteins (neoantigens), shows the existence of a continuous immune response, which might account for the patient's much reduced lung, liver and skin metastases.

Although immune identification of neoantigens has the ability to eradicate growing tumors, in this instance there has been therapeutic resistance. The genetic inactivation of the MHC class 1 2 microglobulin component, which is very common in numerous tumour types, including melanomas, is one of the suggested mechanisms that helps tumors evade the immune system onslaught. Therefore, the upregulation of tumourassociated antigens and/or the emergence of neoantigens will not inhibit tumor progression via TCR-activated T cells in patients with defective antigen presentation [10].

As a result, evaluating the functioning of antigen presentation pathways in tumor cells is necessary for a vaccination idea based on neoantigens [11]. IDO has also been suggested as a possible mechanism for the immunosuppression caused by melanoma. According to this theory, Allison and colleagues showed that IDO can reduce tumour-infiltrating effector T-cells while favoring the expansion of Treg cells, which can limit antitumor responses in the setting of ipilimumab treatment [12]. Therefore, combination therapies utilizing siRNA technology or 1-methyl-tryptophan, which are now in Phase I clinical studies, are urgently needed.

Conclusion

This case report highlights the clinical response and immunological changes observed in a patient with metastatic melanoma treated with combination therapy comprising ipilimumab and an IDO-silenced dendritic cell vaccine. The diversification and potentiation of the antitumour immune response demonstrated the potential efficacy of this therapeutic approach. Further research and larger clinical studies are warranted to validate these findings and optimize treatment strategies for metastatic melanoma.

Competing Interest

The authors declare no competing interests.

References

1. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245-252.

   [Crossref] [Google scholar] [PubMed]

2. Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012;12(4):265-277.

   [Crossref] [Google scholar] [PubMed]

3. Hoos A, Britten CM, Huber C, O'Donnell-Tormey J. A methodological framework to enhance the clinical success of cancer immunotherapy. Nat Biotechnol. 2011;29(10):867-870.

   [Crossref] [Google scholar] [PubMed]

4. Guo C, Manjili MH, Subjeck JR, Sarkar D, Fisher PB, Wang XY. Therapeutic cancer vaccines: past, present, and future. Adv Cancer Res. 2013;119:421-475.

   [Crossref] [Google scholar] [PubMed]

5. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21(1):685-711.

   [Crossref] [Google scholar] [PubMed]

6. Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest. 2007;117(5):1147-1154.

   [Crossref] [Google scholar] [PubMed]

7. Hubert P, Jacobs N, Caberg JH, Boniver J, Delvenne P. The cross-talk between dendritic and regulatory T cells: good or evil?. J Leukoc Biol. 2007;82(4):781-794.

   [Crossref] [Google scholar] [PubMed]

8. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4(10):762-774.

   [Crossref] [Google scholar] [PubMed]

9. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236(1):219-242.

   [Crossref] [Google scholar] [PubMed]

10. Dennis KL, Blatner NR, Gounari F, Khazaie K. Current status of IL-10 and regulatory T-cells in cancer. Curr Opin Oncol. 2013;25(6):637-645.

    [Crossref] [Google scholar] [PubMed]

11. Hwu P, Du MX, Lapointe R, Do M, Taylor MW, Young HA. Indoleamine 2, 3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol. 2000;164(7):3596-3599.

    [Crossref] [Google scholar] [PubMed]

12. Wobser M, Voigt H, Houben R, Eggert AO, Freiwald M, Kaemmerer U, et al. Dendritic cell based antitumor vaccination: impact of functional indoleamine 2, 3-dioxygenase expression. Cancer Immunol Immunother. 2007;56:1017-1024.

    [Crossref] [Google scholar] [PubMed]