Therapeutic HPV Cancer Vaccine Targeted to CD40 Elicits Effective CD8+ T-cell Immunity

Yin, Wu; Duluc, Dorothée; Joo, HyeMee; Xue, Yaming; Gu, Chao; Wang, Zhiqing; Wang, Lei; Ouedraogo, Richard; Oxford, Lance; Clark, Amelia; Parikh, Falguni; Kim‐Schulze, Seunghee; Thompson-Snipes, LuAnn; Lee, Sang‐Yull; Beauregard, Clay; Woo, Jung-Hee; Zurawski, Sandra; Sikora, Andrew G.; Zurawski, Gérard; Oh, SangKon

doi:10.1158/2326-6066.cir-16-0128

Cited by 23 publications

(33 citation statements)

References 48 publications

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“…In our recent studies [29,30] , we have further demonstrated the proof of concept that strongly support the clinical development of CD40-targeting therapeutic vaccines for HPV16-associated cancers using our prototype vaccine, anti-CD40-HPV16.E6/7 protein.…”

Section: Research Highlightmentioning

confidence: 57%

“…Critical findings in our recent study [30] with a prototype vaccine for HPV16-associated malignancies, anti-CD40-HPV16.E6/7, include that it can evoke HPV16.E6/7-specific CD8 + and CD4 + T cell responses in head-and-neck cancer patients in vitro and in human CD40 transgenic (hCD40tg) mice in vivo. The combination of anti-CD40-HPV16.E6/7 and poly(I:C) efficiently primed HPV16.E6/7-specific T cells, particularly CD8 + T cells, in hCD40tg mice and could thus mount therapeutic immunity against challenged tumors.…”

Section: Malignant Transformation Of Hpv-infected Cells Is Drivenmentioning

confidence: 89%

“…Multiple candidate vaccines targeting E6/7 are currently under development, including E6-and/or E7-derived peptide [42][43][44][45] , protein [46,47] , plasmid [48,49] and live-vectored vaccines [50][51][52][53] . Nevertheless, potential safety concerns for some of these vaccine models, especially for immunocompromised individuals, and the overall weak CD8 + CTL-mediated immunity -remain major challenges in developing a safe and effective vaccine against HPV-associated malignancies [54][55][56] .Critical findings in our recent study [30] with a prototype vaccine for HPV16-associated malignancies, anti-CD40-HPV16.E6/7, include that it can evoke HPV16.E6/7-specific CD8 + and CD4 + T cell responses in head-and-neck cancer patients in vitro and in human CD40 transgenic (hCD40tg) mice in vivo. The combination of anti-CD40-HPV16.E6/7 and poly(I:C) efficiently primed HPV16.E6/7-specific T cells, particularly CD8 + T cells, in hCD40tg mice and could thus mount therapeutic immunity against challenged tumors.…”

mentioning

confidence: 80%

“…These factors include 1) selection of proper adjuvant, 2) route of immunization, 3) finding strategies to promote effector CD8 + T cell migration into mucosal tissues, and 4) finding strategies to efficiently counteract tumor immune evasion mechanisms. Throughout our studies [30] , we have used poly(I:C) as an adjuvant, and this decision was based on our human in vitro data [30] and mouse in vivo data from previous studies [57,58] . Recent studies in NHPs and humans have also shown that poly(I:C) and it's derivative poly-ICLC are safe [59] and can thus be used as an adjuvant for our prototype vaccine for HPV16-associated cancers.…”

Section: Malignant Transformation Of Hpv-infected Cells Is Drivenmentioning

confidence: 99%

mentioning

confidence: 99%

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Dendritic Cell Targeting Vaccine for HPV-Associated Cancer

Yin

Duluc

Joo

et al. 2017

Can Cell Microenviron

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Dendritic cells (DCs) are major antigen presenting cells that can efficiently prime and activate cellular immune responses. Delivering antigens to in vivo DCs has thus been considered as a promising strategy that could allow us to mount T cell-mediated therapeutic immunity against cancers in patients.Successful development of such types of cancer vaccines that can target in vivo DCs, however, requires a series of outstanding questions that need to be addressed. These include the proper selection of which DC surface receptors, specific DC subsets and DC activators that can further enhance the efficacy of vaccines by promoting effector T cell infiltration and retention in tumors and their actions against tumors. Supplementing these areas of research with additional strategies that can counteract tumor immune evasion mechanisms is also expected to enhance the efficacy of such therapeutic vaccines against cancers. After more than a decade of study, we have concluded that antigen targeting to DCs via CD40 to evoke cellular responses is more efficient than targeting antigens to the same types of DCs via eleven other DC surface receptors tested. In recent work, we have further demonstrated that a prototype vaccine (anti-CD40-HPV16.E6/7, a recombinant fusion protein of anti-human CD40 and HPV16.E6/7 protein) for HPV16-associated cancers can efficiently activate HPV16.E6/7-specific T cells, particularly CD8 + T cells, from the blood of HPV16 + head-and-neck cancer patients. Moreover, anti-CD40-HPV16.E6/7 plus poly(I:C) can mount potent therapeutic immunity against TC-1 tumor expressing HPV16.E6/7 protein in human CD40 transgenic mice. In this manuscript, we thus highlight our recent findings for the development of novel CD40 targeting immunotherapeutic vaccines for HPV16-associated malignancies. In addition, we further discuss several of key questions that still remain to be addressed for enhancing therapeutic immunity elicited by our prototype vaccine against HPV16-associated malignancies. Dendritic cells (DCs) are the major antigen presenting cells (APCs) that can efficiently cross-prime antigen-specific CD8 + T cells [1,2] . Such functional specialty in turn makes DCs the ideal cellular targets for the rational design of vaccine against cancers. In line with these notions, Bonifaz et al. demonstrated that antigen targeting to in vivo DCs via DEC-205 using conjugates of anti-DEC-205 and antigen is far more efficient than antigen alone at eliciting antigen-specific cellular immunity [3] .For more than a decade after the initial report on DC targeting vaccines [3] , groups of scientists have been trying to RESEARCH HIGHLIGHTCancer Cell & Microenvironment 2016; 3: e1482. doi: 10.14800/ccm.1482; © 2016 by Wenjie Yin, et al.Page 2 of 6 optimize DC-targeting vaccines by delivering antigens to different DC surface receptors. These receptors include c-type lectins (e.g., DEC205, DC-SIGN, CD207, LOX-1, DC-ASGPR, Dectin-1, DCIR, DCIR2, CLEC6, CLEC9A, and CLEC12A) [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][...

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Section: Research Highlightmentioning

confidence: 57%

Section: Malignant Transformation Of Hpv-infected Cells Is Drivenmentioning

confidence: 89%

mentioning

confidence: 80%

Section: Malignant Transformation Of Hpv-infected Cells Is Drivenmentioning

confidence: 99%

mentioning

confidence: 99%

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Dendritic Cell Targeting Vaccine for HPV-Associated Cancer

Yin

Duluc

Joo

et al. 2017

Can Cell Microenviron

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The human anti-CD40 agonist antibody mitazalimab (ADC-1013; JNJ-64457107) activates antigen-presenting cells, improves expansion of antigen-specific T cells, and enhances anti-tumor efficacy of a model cancer vaccine in vivo

Deronic

Nilsson

Thagesson

et al. 2021

Cancer Immunol Immunother

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Non-responders to checkpoint inhibitors generally have low tumor T cell infiltration and could benefit from immunotherapy that activates dendritic cells, with priming of tumor-reactive T cells as a result. Such therapies may be augmented by providing tumor antigen in the form of cancer vaccines. Our aim was to study the effects of mitazalimab (ADC-1013; JNJ-64457107), a human anti-CD40 agonist IgG1 antibody, on activation of antigen-presenting cells, and how this influences the priming and anti-tumor potential of antigen-specific T cells, in mice transgenic for human CD40. Mitazalimab activated splenic CD11c+ MHCII+ dendritic cells and CD19+ MHCII+ B cells within 6 h, with a return to baseline within 1 week. This was associated with a dose-dependent release of proinflammatory cytokines in the blood, including IP-10, MIP-1α and TNF-α. Mitazalimab administered at different dose regimens with ovalbumin protein showed that repeated dosing expanded ovalbumin peptide (SIINFEKL)-specific CD8+ T cells and increased the frequency of activated ICOS+ T cells and CD44hi CD62L− effector memory T cells in the spleen. Mitazalimab prolonged survival of mice bearing MB49 bladder carcinoma tumors and increased the frequency of activated granzyme B+ CD8+ T cells in the tumor. In the ovalbumin-transfected tumor E.G7-OVA lymphoma, mitazalimab administered with either ovalbumin protein or SIINFEKL peptide prolonged the survival of E.G7-OVA tumor-bearing mice, as prophylactic and therapeutic treatment. Thus, mitazalimab activates antigen-presenting cells, which improves expansion and activation of antigen-specific T cells and enhances the anti-tumor efficacy of a model cancer vaccine.

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