Maximizing cancer therapy via complementary mechanisms of immune activation: PD-1 blockade, neoantigen vaccination, and Tregs depletion

D’Alise, Anna Morena; Leoni, Guido; Lucia, Maria De; Langone, Francesca; Nocchi, Linda; Tucci, Fabio Giovanni; Micarelli, Elisa; Cotugno, Gabriella; Troise, Fulvia; Garzia, Irene; Vitale, Rosa; Bignone, Veronica; Matteo, Elena Di; Bartolomeo, Rosa; Charych, Deborah H.; Lahm, Armin; Zalevsky, Jonathan; Nicosia, Alfredo; Scarselli, Elisa

doi:10.1136/jitc-2021-003480

Cited by 7 publications

(5 citation statements)

References 29 publications

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“…IL-2, the first cytokine approved for clinical cancer treatment, was restricted by the proliferation of Tregs expressing high-affinity IL-2Rα (CD25), which hindered anti-tumor immunity. Several structural variants of IL-2 without binding to IL2Rα have been developed, for example, Bempegaldesleukin (BEMPEG: NKTR-214) 169 and Neoleukin-2 (Neo2/15) 170 . A study found that neoantigen vaccination alone was ineffective, BEMPEG monotherapy cured 20% of the mice, and the combination led to tumor regression in half mice.…”

Section: Neoantigen Vaccine and Clinical Applicationmentioning

confidence: 99%

“…A study found that neoantigen vaccination alone was ineffective, BEMPEG monotherapy cured 20% of the mice, and the combination led to tumor regression in half mice. These may be related to the increased level of vaccine-induced T cells and CD8+ T cells infiltration, and the reduced population of Tregs caused by BEMPEG 169 . Furthermore, TLR played an essential role in anti-infective immune responses.…”

Section: Neoantigen Vaccine and Clinical Applicationmentioning

confidence: 99%

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Engineering neoantigen vaccines to improve cancer personalized immunotherapy

Lv¹,

Dang²,

Liu³

et al. 2022

Int. J. Biol. Sci.

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Immunotherapy treatments harnessing the immune system herald a new era of personalized medicine, offering considerable benefits for cancer patients. Over the past years, tumor neoantigens emerged as a rising star in immunotherapy. Neoantigens are tumor-specific antigens arising from somatic mutations, which are proceeded and presented by the major histocompatibility complex on the cell surface. With the advancement of sequencing technology and bioinformatics engineering, the recognition of neoantigens has accelerated and is expected to be incorporated into the clinical routine. Currently, tumor vaccines against neoantigens mainly encompass peptides, DNA, RNA, and dendritic cells, which are extremely specific to individual patients. Due to the high immunogenicity of neoantigens, tumor vaccines could activate and expand antigen-specific CD4+ and CD8+ T cells to intensify anti-tumor immunity. Herein, we introduce the origin and prediction of neoantigens and compare the advantages and disadvantages of multiple types of neoantigen vaccines. Besides, we review the immunizations and the current clinical research status in neoantigen vaccines, and outline strategies for enhancing the efficacy of neoantigen vaccines. Finally, we present the challenges facing the application of neoantigens.

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Section: Neoantigen Vaccine and Clinical Applicationmentioning

confidence: 99%

Section: Neoantigen Vaccine and Clinical Applicationmentioning

confidence: 99%

Engineering neoantigen vaccines to improve cancer personalized immunotherapy

Lv¹,

Dang²,

Liu³

et al. 2022

Int. J. Biol. Sci.

View full text Add to dashboard Cite

show abstract

“…It may also be associated with preexisting and acquired resistance mechanisms that impede T-cell functions and lead to tumor escape from the immune system [ 82 , 83 ]. To bypass resistance mechanisms, neoantigen-based vaccination was combined with the depletion of regulatory T cells (Tregs) in murine cancer models [ 84 ]. In this context, a combination of an IL-2 pathway agonist with Treg-depleting activity with the cancer vaccine led to the activation of neoantigen-specific T cells and a complete eradication of the tumor [ 84 ].…”

Section: Neoantigens As Promising Targets For Cancer Immunotherapymentioning

confidence: 99%

“…To bypass resistance mechanisms, neoantigen-based vaccination was combined with the depletion of regulatory T cells (Tregs) in murine cancer models [ 84 ]. In this context, a combination of an IL-2 pathway agonist with Treg-depleting activity with the cancer vaccine led to the activation of neoantigen-specific T cells and a complete eradication of the tumor [ 84 ]. With regard to the issue of the low frequency of neoantigen-specific T cells, engineered IL-2 receptor (IL-2R) agonists have been designed to expand T lymphocytes and take advantage of IL-2 benefits [ 85 ].…”

Section: Neoantigens As Promising Targets For Cancer Immunotherapymentioning

confidence: 99%

Mutant and non-mutant neoantigen-based cancer vaccines: recent advances and future promises

Ashi

Mami‐Chouaib

Corgnac

2022

Exploration of Targeted Anti-Tumor Therapy

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Major advances in cancer treatment have emerged with the introduction of immunotherapies using blocking antibodies that target T-cell inhibitory receptors, such as programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), known as immune checkpoints. However, most cancer patients do not respond to immune checkpoint blockade (ICB) therapies, suggesting the development of resistance mechanisms associated with either an insufficient number of preexisting tumor-specific T-cell precursors and/or inappropriate T-cell reactivation. To broaden clinical benefit, anti-PD-1/PD-1 ligand (PD-L1) neutralizing antibodies have been combined with therapeutic cancer vaccines based on non-mutant and/or mutant tumor antigens, to stimulate and expand tumor-specific T lymphocytes. Although these combination treatments achieve the expected goal in some patients, relapse linked to alterations in antigen presentation machinery (APM) of cancer cells often occurs leading to tumor escape from CD8 T-cell immunity. Remarkably, an alternative antigenic peptide repertoire, referred to as T-cell epitopes associated with impaired peptide processing (TEIPP), arises on these malignant cells with altered APM. TEIPP are derived from ubiquitous non-mutant self-proteins and represent a unique resource to target immune-edited tumors that have acquired resistance to cytotoxic T lymphocytes (CTLs) related to defects in transporter associated with antigen processing (TAP) and possibly also to ICB. The present review discusses tumor-associated antigens (TAAs) and mutant neoantigens and their use as targets in peptide- and RNA-based therapeutic cancer vaccines. Finally, this paper highlights TEIPP as a promising immunogenic non-mutant neoantigen candidates for active cancer immunotherapy and combination with TAA and mutant neoantigens. Combining these polyepitope cancer vaccines with ICB would broaden T-cell specificity and reinvigorate exhausted antitumor CTL, resulting in the eradication of all types of neoplastic cells, including immune-escaped subtypes.

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“…To this end, vaccine adjuvants were shown to play a fundamental role in increasing vaccine immunological potency and protection. This is achieved by combined administration of vaccine and immune-modulatory molecules, as it has been welldocumented, and found to have broad applications spanning from infectious diseases to cancer (5)(6)(7)(8)(9)(10). Classical vaccines can take advantage from the use of adjuvant compounds, such as aluminum salts, oil in water emulsion, and the more recently approved AS01, AS03, AS04, CpG ODN, and MF59, as a mean to improve magnitude and quality of antigen-specific adaptive immunity for optimized protection against pathogens (11,12).…”

Section: Introductionmentioning

confidence: 99%

Adenovirus Encoded Adjuvant (AdEnA) anti-CTLA-4, a novel strategy to improve Adenovirus based vaccines against infectious diseases and cancer

et al. 2023

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IntroductionVirus vectored genetic vaccines (Vvgv) represent a promising approach for eliciting immune protection against infectious diseases and cancer. However, at variance with classical vaccines to date, no adjuvant has been combined with clinically approved genetic vaccines, possibly due to the detrimental effect of the adjuvant-induced innate response on the expression driven by the genetic vaccine vector. We reasoned that a potential novel approach to develop adjuvants for genetic vaccines would be to “synchronize” in time and space the activity of the adjuvant with that of the vaccine.MethodsTo this aim, we generated an Adenovirus vector encoding a murine anti-CTLA-4 monoclonal antibody (Ad-9D9) as a genetic adjuvant for Adenovirus based vaccines.ResultsThe co-delivery of Ad-9D9 with an Adeno-based COVID-19 vaccine encoding the Spike protein resulted in stronger cellular and humoral immune responses. In contrast, only a modest adjuvant effect was achieved when combining the vaccine with the same anti-CTLA-4 in its proteinaceous form. Importantly, the administration of the adjuvant vector at different sites of the vaccine vector abrogates the immunostimulatory effect. We showed that the adjuvant activity of Ad-α-CTLA-4 is independent from the vaccine antigen as it improved the immune response and efficacy of an Adenovirus based polyepitope vaccine encoding tumor neoantigens.DiscussionOur study demonstrated that the combination of Adenovirus Encoded Adjuvant (AdEnA) with an Adeno-encoded antigen vaccine enhances immune responses to viral and tumor antigens, representing a potent approach to develop more effective genetic vaccines.

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Maximizing cancer therapy via complementary mechanisms of immune activation: PD-1 blockade, neoantigen vaccination, and Tregs depletion

Cited by 7 publications

References 29 publications

Engineering neoantigen vaccines to improve cancer personalized immunotherapy

Engineering neoantigen vaccines to improve cancer personalized immunotherapy

Mutant and non-mutant neoantigen-based cancer vaccines: recent advances and future promises

Adenovirus Encoded Adjuvant (AdEnA) anti-CTLA-4, a novel strategy to improve Adenovirus based vaccines against infectious diseases and cancer

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