gp100209–2M Peptide Immunization of Human Lymphocyte Antigen-A2+ Stage I-III Melanoma Patients Induces Significant Increase in Antigen-Specific Effector and Long-Term Memory CD8+ T Cells

Walker, Edwin; Haley, Daniel; Miller, William L.; Floyd, Kevin; Wisner, Ketura Preya; Sanjuan, Nelson; Maecker, Holden T.; Romero, Pedro; Hu, Hong-Ming; Alvord, W. Gregory; Smith, John W.; Fox, Bernard A.; Urba, Walter J.

doi:10.1158/1078-0432.ccr-0095-03

Cited by 72 publications

(47 citation statements)

References 34 publications

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“…Alternatively, the use of proteins or peptides in combination with adjuvants should be considered: a recent clinical study of repeated injections of peptide and adjuvant has demonstrated continued boosting of CTL responses, reaching levels as high as 8% of CD8 ϩ cells. 47,48 Many preclinical studies have confirmed the ability of recombinant DNA vaccines to prime both humoral and cellular immune responses specific for recombinant gene products in mice and primates. 49 Indeed, we confirmed that DNA.Mel3 primes responses specific for the melan-A 26 -35 , tyrosinase 369 -377 and NY-ESO-1 155-167 epitopes in HLA-A2 transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Recombinant modified vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence

Smith

Dunbar

Mirza

et al. 2004

Intl Journal of Cancer

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Section: Discussionmentioning

confidence: 99%

Recombinant modified vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence

Smith

Dunbar

Mirza

et al. 2004

Intl Journal of Cancer

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“…10 However, these types of vaccines require high amounts of antigens to be effective as they will also be internalized and/or presented by other cells than DCs. [11][12][13][14][15] Additionally, the efficacy of these vaccines is often limited in a therapeutic setting. To enhance cross-presentation of tumor antigens and to achieve a better priming of T cells, current vaccination strategies focus at the in vivo delivery of tumor-antigens as proteins or peptides specifically to DCs.…”

Section: Introductionmentioning

confidence: 99%

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

et al. 2014

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C regulatory T cells (Tregs), resulting in defective T cell priming and failure to induce tumor regression. To circumvent these problems we evaluated a novel combinatorial therapeutic strategy. We show that tumor antigen targeting to DC-SIGN in humanized hSIGN mice via glycans or specific antibodies induces superior T cell priming. Next, this targeted therapy was combined with transient Foxp3 C Treg depletion employing hSIGNxDEREG mice. While Treg depletion alone slightly delayed B16-OVA melanoma growth, only the combination therapy instigated long-term tumor regression in a substantial fraction of mice. This novel strategy resulted in optimal generation of antigen-specific activated CD8C T cells which accumulated in regressing tumors. Notably, Treg depletion also allowed the local appearance of effector T cells specific for endogenous B16 antigens. This indicates that antitumor immune responses can be broadened by therapies aimed at controlling Tregs in tumor environments. Thus, transient inhibition of Treg-mediated immune suppression potentiates DC targeted antigen vaccination and tumor-specific immunity.

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“…A modified epitope, gp209-2M (33), which enhances peptide stability ninefold while not altering pMHC structure (34), is significantly more immunogenic (35) and has been widely used in clinical studies (36,37). Therefore, to closely mimic the clinical situation, we used this modified epitope in all subsequent in vitro and in vivo experiments.…”

mentioning

confidence: 99%

T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy

Shi

Malecek

Johnson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

203

215

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T cells expressing antigen-specific T-cell receptors (TCRs) can mediate effective tumor regression, but they often also are accompanied by autoimmune responses. To determine the TCR affinity threshold defining the optimal balance between effective antitumor activity and autoimmunity in vivo , we used a unique self-antigen system comprising seven human melanoma gp100(209–217)-specific TCRs spanning physiological affinities (1–100 μM). We found that in vitro and in vivo T-cell responses are determined by TCR affinity, except in one case that was compensated by substantial CD8 involvement. Strikingly, we found that T-cell antitumor activity and autoimmunity are closely coupled but plateau at a defined TCR affinity of 10 µM, likely due to diminished contribution of TCR affinity to avidity above the threshold. Together, these results suggest that a relatively low-affinity threshold is necessary for the immune system to avoid self-damage, given the close relationship between antitumor activity and autoimmunity. The low threshold, in turn, indicates that adoptive T-cell therapy treatment strategies using in vitro-generated high-affinity TCRs do not necessarily improve efficacy.

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gp100209–2M Peptide Immunization of Human Lymphocyte Antigen-A2+ Stage I-III Melanoma Patients Induces Significant Increase in Antigen-Specific Effector and Long-Term Memory CD8+ T Cells

Abstract: Thirty-five HLA-A2؉ patients with completely resected stage I-III melanoma were vaccinated multiple times over 6 months with a modified melanoma peptide, gp100 209

Cited by 72 publications

References 34 publications

Recombinant modified vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence

Recombinant modified vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy

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