Adenoviral vaccination combined with CD40 stimulation and CTLA-4 blockage can lead to complete tumor regression in a murine melanoma model

Sørensen, Maria Rathmann; Holst, Peter Johannes; Steffensen, Maria Abildgaard; Christensen, Jan Pravsgaard; Thomsen, Allan Randrup

doi:10.1016/j.vaccine.2010.07.066

Cited by 54 publications

(43 citation statements)

References 40 publications

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“…Similar to the findings of Wang and colleagues (56), Sorensen and colleagues reported melanoma regression and long-term survival rates of 30% to 40% in a study of CTLA4 blockade in combination with CD40 stimulation and the administration of an adenoviral vaccine (62). …”

Section: Vista In Cancersupporting

confidence: 66%

VISTA Is a Novel Broad-Spectrum Negative Checkpoint Regulator for Cancer Immunotherapy

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Sempere

Broughton³

et al. 2014

Cancer Immunology Research

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In the past few years, the field of cancer immunotherapy has made great progress and is finally starting to change the way cancer is treated. We are now learning that multiple negative checkpoint regulators (NCR) restrict the ability of T-cell responses to effectively attack tumors. Releasing these brakes through antibody blockade, first with anti-CTLA4 and now followed by anti-PD1 and anti-PDL1, has emerged as an exciting strategy for cancer treatment. More recently, a new NCR has surfaced called V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation (VISTA). This NCR is predominantly expressed on hematopoietic cells, and in multiple murine cancer models is found at particularly high levels on myeloid cells that infiltrated the tumors. Preclinical studies with VISTA blockade have shown promising improvement in antitumor T-cell responses, leading to impeded tumor growth and improved survival. Clinical trials support combined anti-PD1 and anti-CTLA4 as safe and effective against late-stage melanoma. In the future, treatment may involve combination therapy to target the multiple cell types and stages at which NCRs, including VISTA, act during adaptive immune responses.

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Section: Vista In Cancersupporting

confidence: 66%

VISTA Is a Novel Broad-Spectrum Negative Checkpoint Regulator for Cancer Immunotherapy

Lines

Sempere

Broughton³

et al. 2014

Cancer Immunology Research

196

154

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“…Generally, viruses seem to induce exactly the type of immune response that would be expected to be optimal for efficient tumor control. Consequently, having established an improved platform for anti-infective vaccination using a replication deficient adenovirus, Ad-Ii-GP, we previously tested this vector against tumor cells expressing a viral epitope, namely the LCMV GP (33), and found significant protection (16,59). Notably, this was the case even in hosts expressing the targeted viral epitope as a self-Ag in the pancreas.…”

Section: Discussionmentioning

confidence: 99%

“…cDNA samples were run in triplets, controls with Milli-Q H 2 O or no reverse transcriptase were included, and a 5-fold standard curve titration was run in duplicates. The following primers and probes were used: trp-2 forward, 59 …”

Section: Quantitative Real-time Pcr For Lung Metastasis Of Melanoma Cmentioning

confidence: 99%

Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non–Self-Tumor Antigens: Implications for Cancer Immunotherapy

Pedersen

Sørensen

Buus

et al. 2013

The Journal of Immunology

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It is generally accepted that CD8 T cells play a major role in tumor control, yet vaccination aimed at eliciting potent CD8 T cell responses are rarely efficient in clinical trials. To try and understand why this is so, we have generated potent adenoviral vectors encoding the endogenous tumor Ags (TA) tyrosinase-related protein-2 (TRP-2) and glycoprotein 100 (GP100) tethered to the invariant chain (Ii). Using these vectors, we sought to characterize the self-TA–specific CD8 T cell response and compare it to that induced against non–self-Ags expressed from a similar vector platform. Prophylactic vaccination with adenoviral vectors expressing either TRP-2 (Ad-Ii-TRP-2) or GP100 (Ad-Ii-GP100) had little or no effect on the growth of s.c. B16 melanomas, and only Ad-Ii-TRP-2 was able to induce a marginal reduction of B16 lung metastasis. In contrast, vaccination with a similar vector construct expressing a foreign (viral) TA induced efficient tumor control. Analyzing the self-TA–specific CD8 T cells, we observed that these could be activated to produce IFN-γ and TNF-α. In addition, surface expression of phenotypic markers and inhibitory receptors, as well as in vivo cytotoxicity and degranulation capacity matched that of non–self-Ag–specific CD8 T cells. However, the CD8 T cells specific for self-TAs had a lower functional avidity, and this impacted on their in vivo performance. On the basis of these results and a low expression of the targeted TA epitopes on the tumor cells, we suggest that low avidity of the self-TA–specific CD8 T cells may represent a major obstacle for efficient immunotherapy of cancer.

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“…Many other cancer vaccines have been evaluated, without clear success, but with provocative and encouraging findings for several vaccine approaches [4-7]. Recent advances in checkpoint blockade therapies also offer promise to improve the efficacy of cancer vaccines by blocking cancer-associated immune dysfunction and have been shown to be safe when administered in combination with cancer vaccines [8-9]. …”

Section: Introductionmentioning

confidence: 99%

Defining the effects of age and gender on immune response and outcomes to melanoma vaccination: a retrospective analysis of a single-institution clinical trials’ experience

Ramirez

Wages

et al. 2015

Cancer Immunol Immunother

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Background The impacts of patient age and gender on immune response (IR) and clinical outcome after cancer vaccines are not known. We hypothesized younger and female patients would have higher IR rates and better survival. Methods Patients with resected stage IIB-IV melanoma in three clinical trials (Mel43, Mel44, Mel48) were vaccinated with 12 melanoma-associated peptides restricted by Class I MHC. The cumulative incidence rate of CD8+ T cell responses (direct Interferon-gamma ELIspot assay) by week 7 was compared by age and gender. Overall survival (OS) and disease-free survival (DFS) landmark analyses were compared by Kaplan-Meier estimates and in multivariate analyses. Results T cell responses were evaluated in 327 patients, and detected in 50% of males and 48% of females, with no difference in IR by gender or menopausal status. Males had trends toward longer DFS (p=0.12) and OS (p=0.09). Cumulative incidence of IR was higher in patients < 64 years of age versus older patients (p=0.03). OS and DFS were similar by age group (p> 0.50). In multivariate modeling, younger age was associated with better IR (OR 0.40, p-value 0.003), without an impact of age or gender on clinical outcomes. Conclusion These data support the hypothesis that older patients are less likely to develop T cell responses to a cancer vaccine. Nonetheless, significant proportions of older patients mount immune responses with comparable survival outcomes. Thus, these data support including older patients in cancer vaccine trials, but suggest value in stratifying patients by age < / > 64 years.

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Adenoviral vaccination combined with CD40 stimulation and CTLA-4 blockage can lead to complete tumor regression in a murine melanoma model

Cited by 54 publications

References 40 publications

VISTA Is a Novel Broad-Spectrum Negative Checkpoint Regulator for Cancer Immunotherapy

VISTA Is a Novel Broad-Spectrum Negative Checkpoint Regulator for Cancer Immunotherapy

Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non–Self-Tumor Antigens: Implications for Cancer Immunotherapy

Defining the effects of age and gender on immune response and outcomes to melanoma vaccination: a retrospective analysis of a single-institution clinical trials’ experience

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