Generation of MANAbodies specific to HLA-restricted epitopes encoded by somatically mutated genes

Skora, Andrew D.; Douglass, Jacqueline; Hwang, Michael S.; Tam, Ada; Blosser, Richard L.; Gabelli, Sandra B.; Cao, Jianhong; Díaz, Luis A.; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Zhou, Shibin

doi:10.1073/pnas.1511996112

Cited by 47 publications

(68 citation statements)

References 59 publications

(64 reference statements)

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“…Given that radiation enhances cross-priming of antigen-specific CD8+ effector T-cells primarily within the tumor-associated DLN [14–15], we queried whether T + LN RT (ENI) alters the effector function of antigen-specific T-cells in the tumor microenvironment. For these experiments, we used MC38-OVA and B16-OVA tumors - with the notion that in this system, OVA models a mutation-associated neo-antigen (MANA) to which high-affinity T-cells may exist [33]. To quantify antigen-specific T-cell responses, we performed adoptive transfer experiments in which naïve CFSE-labeled OVA-specific CD8+ T-cells (OT-1) were transferred into host mice bearing OVA-expressing tumors 48 hours after stereotactic RT.…”

Section: Resultsmentioning

confidence: 99%

Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy

Marciscano

Ghasemzadeh

Nirschl

et al. 2018

Clinical Cancer Research

233

147

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In the proper context, radiotherapy can promote antitumor immunity. It is unknown if elective nodal irradiation (ENI), a strategy that irradiates tumor-associated draining lymph nodes (DLN), affects adaptive immune responses and combinatorial efficacy of radiotherapy with immune checkpoint blockade (ICB). We developed a preclinical model to compare stereotactic radiotherapy (Tumor RT) with or without ENI to examine immunologic differences between radiotherapy techniques that spare or irradiate the DLN. Tumor RT was associated with upregulation of an intratumoral T-cell chemoattractant chemokine signature (CXCR3, CCR5-related) that resulted in robust infiltration of antigen-specific CD8 effector T cells as well as FoxP3 regulatory T cells (Tregs). The addition of ENI attenuated chemokine expression, restrained immune infiltration, and adversely affected survival when combined with ICB, especially with anti-CLTA4 therapy. The combination of stereotactic radiotherapy and ICB led to long-term survival in a subset of mice and was associated with favorable CD8 effector-to-Treg ratios and increased intratumoral density of antigen-specific CD8 T cells. Although radiotherapy technique (Tumor RT vs. ENI) affected initial tumor control and survival, the ability to reject tumor upon rechallenge was partially dependent upon the mechanism of action of ICB; as radiotherapy/anti-CTLA4 was superior to radiotherapy/anti-PD-1. Our results highlight that irradiation of the DLN restrains adaptive immune responses through altered chemokine expression and CD8 T-cell trafficking. These data have implications for combining radiotherapy and ICB, long-term survival, and induction of immunologic memory. Clinically, the immunomodulatory effect of the radiotherapy strategy should be considered when combining stereotactic radiotherapy with immunotherapy. .

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Section: Resultsmentioning

confidence: 99%

Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy

Marciscano

Ghasemzadeh

Nirschl

et al. 2018

Clinical Cancer Research

233

147

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“…MANAs are critical inducers of T cell-mediated anticancer immune response (1,24). Consequently, various immunotherapeutic approaches targeting defined MANAs have been developed (4,8,(25)(26)(27)(28). Given the efforts and time needed to develop the therapeutic agents against the target MANAs, it is imperative that the presentation on tumor cell surface of the predicted MANAs be verified before such efforts are initiated.…”

Section: Discussionmentioning

confidence: 99%

Direct Detection and Quantification of Neoantigens

Wang

Douglass

Hwang

et al. 2019

Cancer Immunology Research

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Many immunotherapeutic approaches under development rely on T-cell recognition of cancer-derived peptides bound to human leukocyte antigen molecules on the cell surface. Direct experimental demonstration that such peptides are processed and bound is currently challenging. Here, we describe a method that meets this challenge. The method entailed an optimized immunoprecipitation protocol coupled with twodimensional chromatography and mass spectrometry. The ability to detect and quantify minute amounts of predefined antigens should be useful both for basic research in tumor immunology and for the development of rationally designed cancer vaccines.

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“…Subsequent identification of antigen-specific clones usually requires screening of hundreds or even thousands of clones [39,81,84]. Additionally, such factors as low immunogenicity, few unique clones due to immunodominance, and poor control of fine-specificity have been hampering antibody discovery through this route [57,71]. An advantage of hybridoma technology is the potential for natural affinity maturation, which often results in higher affinity mAbs.…”

Section: Antibodies With Specificity For Pmhc Moleculesmentioning

confidence: 99%

Targeting the MHC Ligandome by Use of TCR-Like Antibodies

et al. 2019

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Monoclonal antibodies (mAbs) are valuable as research reagents, in diagnosis and in therapy. Their high specificity, the ease in production, favorable biophysical properties and the opportunity to engineer different properties make mAbs a versatile class of biologics. mAbs targeting peptide–major histocompatibility molecule (pMHC) complexes are often referred to as “TCR-like” mAbs, as pMHC complexes are generally recognized by T-cell receptors (TCRs). Presentation of self- and non-self-derived peptide fragments on MHC molecules and subsequent activation of T cells dictate immune responses in health and disease. This includes responses to infectious agents or cancer but also aberrant responses against harmless self-peptides in autoimmune diseases. The ability of TCR-like mAbs to target specific peptides presented on MHC allows for their use to study peptide presentation or for diagnosis and therapy. This extends the scope of conventional mAbs, which are generally limited to cell-surface or soluble antigens. Herein, we review the strategies used to generate TCR-like mAbs and provide a structural comparison with the analogous TCR in pMHC binding. We further discuss their applications as research tools and therapeutic reagents in preclinical models as well as challenges and limitations associated with their use.

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Generation of MANAbodies specific to HLA-restricted epitopes encoded by somatically mutated genes

Cited by 47 publications

References 59 publications

Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy

Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy

Direct Detection and Quantification of Neoantigens

Targeting the MHC Ligandome by Use of TCR-Like Antibodies

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