&lt;p&gt;Potential of Pembrolizumab in Metastatic or Recurrent Head and Neck Cancer: Evidence to Date&lt;/p&gt;

McCusker, Michael G.; Orkoulas-Razis, Dennis; Mehra, Ranee

doi:10.2147/ott.s196252

Cited by 29 publications

(29 citation statements)

References 87 publications

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“…We have previously shown that therapeutic vaccination with an HPV16 L2E7E6 fusion protein, TA-CIN, in the TC-1 tumor model upregulated PD-L1 on tumor cells and PD-1 on circulating CD8 1 T cells (47). Other groups have also reported that HPV-associated cancers tend to be associated with upregulated PD-L1 and enhanced responses to immune checkpoint blockades (35,(48)(49)(50). Furthermore, PD-1/PD-L1 blockade has been used in conjunction with other cancer vaccines to improve therapeutic effects (51,52).…”

Section: Discussionmentioning

confidence: 98%

“…The FDA has approved pembrolizumab (KEYTRUDA) for use in cervical cancer patients, and several other ongoing clinical trials are investigating the safety and efficacy of other checkpoint-blocking antibodies in cervical cancer (for review, see reference 34). In general, immune checkpoint-blocking antibodies have demonstrated some degree of efficacy against cervical cancer and HPV-associated head and neck cancers (35,46). Elevated levels of PD-L1/PD-1 tend to be associated with better clinical responses to immune checkpoint blockade.…”

Section: Discussionmentioning

confidence: 99%

“…PD-1 antibody blockade improves outcomes for a fraction of cervical cancer patients (for review, see reference 34). Failure of this treatment may be due to several factors, such as absent expression of PD-L1/PD-1 or a poor immune response (35). However, the best response to this immunotherapy is associated with a robust prior CD8 1 T cell infiltrate (36,37).…”

mentioning

confidence: 99%

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Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Peng

Gaillard

Wang

et al. 2021

mBio

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Immunotherapy for cervical cancer should target high-risk human papillomavirus types 16 and 18, which cause 50% and 20% of cervical cancers, respectively. Here, we describe the construction and characterization of the pBI-11 DNA vaccine via the addition of codon-optimized human papillomavirus 18 (HPV18) E7 and HPV16 and 18 E6 genes to the HPV16 E7-targeted DNA vaccine pNGVL4a-SigE7(detox)HSP70 (DNA vaccine pBI-1). Codon optimization of the HPV16/18 E6/E7 genes in pBI-11 improved fusion protein expression compared to that in DNA vaccine pBI-10.1 that utilized the native viral sequences fused 3′ to a signal sequence and 5′ to the HSP70 gene of Mycobacterium tuberculosis. Intramuscular vaccination of mice with pBI-11 DNA better induced HPV antigen-specific CD8+ T cell immune responses than pBI-10.1 DNA. Furthermore, intramuscular vaccination with pBI-11 DNA generated stronger therapeutic responses for C57BL/6 mice bearing HPV16 E6/E7-expressing TC-1 tumors. The HPV16/18 antigen-specific T cell-mediated immune responses generated by pBI-11 DNA vaccination were further enhanced by boosting with tissue-antigen HPV vaccine (TA-HPV). Combination of the pBI-11 DNA and TA-HPV boost vaccination with PD-1 antibody blockade significantly improved the control of TC-1 tumors and extended the survival of the mice. Finally, repeat vaccination with clinical-grade pBI-11 with or without clinical-grade TA-HPV was well tolerated in vaccinated mice. These preclinical studies suggest that the pBI-11 DNA vaccine may be used with TA-HPV in a heterologous prime-boost strategy to enhance HPV 16/18 E6/E7-specific CD8+ T cell responses, either alone or in combination with immune checkpoint blockade, to control HPV16/18-associated tumors. Our data serve as an important foundation for future clinical translation. IMPORTANCE Persistent expression of high-risk human papillomavirus (HPV) E6 and E7 is an obligate driver for several human malignancies, including cervical cancer, wherein HPV16 and HPV18 are the most common types. PD-1 antibody immunotherapy helps a subset of cervical cancer patients, and its efficacy might be improved by combination with active vaccination against E6 and/or E7. For patients with HPV16+ cervical intraepithelial neoplasia grade 2/3 (CIN2/3), the precursor of cervical cancer, intramuscular vaccination with a DNA vaccine targeting HPV16 E7 and then a recombinant vaccinia virus expressing HPV16/18 E6-E7 fusion proteins (TA-HPV) was safe, and half of the patients cleared their lesions in a small study (NCT00788164). Here, we sought to improve upon this therapeutic approach by developing a new DNA vaccine that targets E6 and E7 of HPV16 and HPV18 for administration prior to a TA-HPV booster vaccination and for application against cervical cancer in combination with a PD-1-blocking antibody.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Peng

Gaillard

Wang

et al. 2021

mBio

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“…Pembrolizumab has been used to treat certain kinds of cancer with varying degrees of effectiveness. Pembrolizumab has shown promising results in metastatic melanoma, metastatic non-small cell lung cancer in several clinical trials, and most recently approved for the treatment of squamous cell cancer in the head and neck (HNSCC) [ 163 ].…”

Section: Prospective Clinical Trialsmentioning

confidence: 99%

Biomarkers and novel therapeutic approaches for diffuse large B-cell lymphoma in the era of precision medicine

et al. 2020

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Despite the great efforts for better treatment options for diffuse large B-cell lymphoma (DLBCL) (most common form of non-Hodgkin lymphoma, NHL) to treat and prevent relapse, it continues to be a challenge. Here, we present an overview of DLBCL and address the diagnostic assays and molecular techniques used in its diagnosis, role of biomarkers in detection, treatment of early and advanced stage DLBCL, and novel drug regimens. We discuss the significant biomarkers that have emerged as essential tools for stratifying patients according to risk factors and for providing insights into the use of more targeted and individualized therapeutics. We discuss techniques such as gene expression studies, including next-generation sequencing, which have enabled a more understanding of the complex pathogenesis of DLBCL and have helped determine molecular targets for novel therapeutic agents. We examine current treatment approaches, outline the findings of completed clinical trials, and provide updates for ongoing clinical trials. We highlight clinical trials relevant to the significant fraction of DLBCL patients who present with complex cases marked by high relapse rates. Supported by an increased understanding of targetable pathways in DLBCL, clinical trials involving specialized combination therapies are bringing us within reach the promise of an effective cure to DLBCL using precision medicine. Optimization of therapy remains a crucial objective, with the end goal being a balance between high survival rates through targeted and personalized treatment while reducing adverse effects in DLBCL patients of all subsets.

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“…Few targeted molecular therapies include epidermal growth factor (EGF-R) receptor inhibitor (cetuximab) for HNSCCs [5,6] and antibody to VEGF (bevacizumab) for CvSCC [7]. Recently, immune checkpoint inhibitors (pembrolizumab and nivolumab) are being used for the treatment of HNSCCs, LSCCs and CvSCCs [6][7][8][9].…”

Section: Molecular Landscape Of Sccsmentioning

confidence: 99%

The Impact of the Ubiquitin System in the Pathogenesis of Squamous Cell Carcinomas

Gatti

Bernassola

Talora

et al. 2020

Cancers

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The ubiquitin system is a dynamic regulatory pathway controlling the activity, subcellular localization and stability of a myriad of cellular proteins, which in turn affects cellular homeostasis through the regulation of a variety of signaling cascades. Aberrant activity of key components of the ubiquitin system has been functionally linked with numerous human diseases including the initiation and progression of human tumors. In this review, we will contextualize the importance of the two main components of the ubiquitin system, the E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs), in the etiology of squamous cell carcinomas (SCCs). We will discuss the signaling pathways regulated by these enzymes, emphasizing the genetic and molecular determinants underlying their deregulation in SCCs.

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<p>Potential of Pembrolizumab in Metastatic or Recurrent Head and Neck Cancer: Evidence to Date</p>

Cited by 29 publications

References 87 publications

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody

Biomarkers and novel therapeutic approaches for diffuse large B-cell lymphoma in the era of precision medicine

The Impact of the Ubiquitin System in the Pathogenesis of Squamous Cell Carcinomas

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