Anti‐laminin‐γ1 pemphigoid in an epitope spreading phenomenon, successfully treated with rituximab

2021 ◽  
Author(s):  
Zi Teng Chai ◽  
Yen Loo Lim ◽  
Inny Busmanis ◽  
Shiu Ming Pang
Keyword(s):  
Epitope Spreading

108 MCY-M11, a CAR-PBMC cell product transiently expressing a mesothelin targeted mRNA CAR, exhibits desirable functional and immune phenotype attributed to sustained antitumor immunity in vitro

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A120-A120
Author(s):  
Sashi Kasimsetty ◽  
Himavanth Gatla ◽  
Dhana Chinnasamy
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Memory T Cells ◽  
Cell Populations ◽  
Epitope Spreading ◽  
Antitumor Response ◽  
Cell Product

BackgroundMCY-M11, an anti-mesothelin CAR (Meso-CAR) mRNA transfected PBMC cell product manufactured through <1 day-process is under clinical evaluation for the treatment of advanced ovarian cancer and peritoneal mesothelioma. In this in-vitro study, we characterized the phenotypic and functional status of immune cell populations in MCY-M11 and their possible role in antitumor immunity.MethodsMCY-M11 cell product were generated using unmanipulated healthy donor PBMCs (n=5) by transfection of Meso-CAR mRNA using MaxCyte’s proprietary Flow Electroporation® system. Frozen MCY-M11 cell product was thawed and cultured for 18 hours, then co-cultured with hMSLNneg or hMSLNpos human mesothelioma cell line, MSTO-211H, or stimulated with anti-CD3/anti-CD28 antibodies in vitro for 8 days. Distinct cell populations in MCY-M11 were evaluated for kinetics and duration of CAR expression, differentiation, activation, exhaustion, and their ability to secrete various immunomodulatory molecules during in vitro stimulation. Antigen-specific proliferation and cytotoxicity of MCY-M11 against hMSLNpos tumor cells as well as their ability to mount long-term antitumor immunity through epitope spreading mechanisms were studied.ResultsIndividual cell populations in MCY-M11 exhibited a consistent but transient Meso-CAR expression persisting for about 7 days. Cell subsets in MCY-M11 acquired early signs of activation and differentiation within 18–24 hours post-culture, but only attained full activation and lineage-specific differentiation upon specific response to hMSLNpos tumor cells. hMSLN antigen experienced MCY-M11 retained significant fractions of Naïve and Central Memory T cells and increased percentage of Effector Memory T cells along with increased expression of CD62L, CD27, and chemokine receptors (CCR5, CCR7, and CXCR3). MCY-M11 exhibited strong antigen-specific cytotoxicity against hMSLNpos tumor cells with corresponding increase in activation and proliferation of CD4+ and CD8+ T cell subsets and displayed low or no acquisition of known exhaustion markers. NK cells also exhibited a functionally superior molecular signature exhibiting increased levels of NKG2D, NKp44, NKp46, FAS, and TRAIL. The Monocytes and B cells in MCY-M11 also acquired an activated, differentiated, and mature phenotype, expressing molecules required for antigen presentation (HLA-DR, HLA-ABC, and CD205) and T cell co-stimulation (CD80 and CD86) to mount a strong antitumor response. These phenotypic changes in cell subsets of MCY-M11 transpired with simultaneous secretion of potent immunostimulatory molecules and chemokines facilitating an extended antitumor response through epitope spreading.ConclusionsWe demonstrated that MCY-M11 is a unique cell product possessing a complete built-in immune cellular machinery with favorable phenotype and enhanced functions specialized in mediating an effective and long-term antitumor response.Trial RegistrationNCT03608618

scholarly journals Epitope Spreading: Lessons From Autoimmune Skin Diseases

1998 ◽  
Vol 110 (2) ◽  
pp. 103-109 ◽  
Author(s):  
Lawrence S. Chan ◽  
Carol J. Vanderlugt ◽  
Takashi Hashimoto ◽  
Takeji Nishikawa ◽  
John J. Zone ◽  
...  
Keyword(s):  
Skin Diseases ◽  
Epitope Spreading

132 CAR macrophages (CAR-M) elicit a systemic anti-tumor immune response and synergize with PD1 blockade in immunocompetent mouse models of HER2+ solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A145-A145
Author(s):  
Stefano Pierini ◽  
Rashid Gabbasov ◽  
Linara Gabitova ◽  
Yumi Ohtani ◽  
Michael Klichinsky
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Animal Model ◽  
T Cell ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Tumor Model ◽  
Epitope Spreading ◽  
Mhc I ◽  
Single Tumor

BackgroundDespite the remarkable efficacy achieved by CAR-T therapy in hematologic malignancies, application in solid tumors has been challenging. We previously developed human CAR-M and demonstrated that adoptive cell transfer of CAR-M into xenograft models of human cancer controls tumor progression and improves overall survival [1]. Given that CAR-M are professional antigen presenting cells, we developed an immunocompetent animal model to evaluate the potential for induction of a systemic anti-tumor immune response.MethodsMurine bone marrow-derived macrophages were engineered to express an anti-HER2 CAR using the chimeric adenoviral vector Ad5f35. CAR-M were phenotypically and functionally evaluated in vitro and in syngeneic models. To evaluate CAR-M efficacy in an immunocompetent animal model, BALB/c mice were engrafted with CT26-HER2+ tumors (single-tumor model) and were treated with intratumoral CAR-HER2 or untransduced (UTD) macrophages. To evaluate epitope spreading, we simultaneously engrafted BALB/c mice with CT26-HER2+ and CT26-Wt tumors on opposite flanks (dual-tumor model), and treated mice with CAR-M or controls into the CT26-HER2+ tumor only. Peripheral and tumor-infiltrating immune cells were phenotypically and functionally characterized.ResultsIn addition to efficient gene delivery, Ad5f35 transduction promoted a pro-inflammatory (M1) phenotype in murine macrophages. CAR-M, but not control UTD macrophages, phagocytosed HER2+ target cancer cells. Anti-HER2 CAR-M eradicated HER2+ murine CT26 colorectal and human AU-565 breast cancer cells in a dose-dependent manner. CAR-M increased MHC-I and MHC-II expression on tumor cells and promoted tumor-associated antigen presentation and T cell activation. In vivo, CAR-M treatment led to tumor regression and improved overall survival in the CT26-HER2+ single-tumor model. In the dual-tumor model, CAR-M treatment cleared 75% of CT26-HER2+ tumors and inhibited the growth rate of contralateral CT26-WT tumors, demonstrating an abscopal effect. CAR-M treatment led to increased infiltration of intratumoral CD4+ and CD8+ T, NK, and dendritic cells – as well as an increase in T cell responsiveness to the CT26 MHC-I antigen gp70, indicating enhanced epitope spreading. Given the impact CAR-M had on endogenous T-cell immunity, we evaluated the combination of CAR-M and anti-PD1 in the CT26-HER2 model and found that the combination further enhanced tumor control and overall survival.ConclusionsThese results demonstrate that CAR-M therapy induces epitope spreading via activation of endogenous T cells, orchestrating a systemic immune response against solid tumors. Moreover, our findings provide rationale for the combination of CAR-M with immune checkpoint inhibitors. The anti-HER2 CAR-M CT-0508 will be evaluated in an upcoming Phase I clinical trial.ReferenceKlichinsky M, Ruella M, Shestova O, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol 2020;38(8):947–953.

scholarly journals Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma

2021 ◽  
Author(s):  
Zhuting Hu ◽  
Donna E. Leet ◽  
Rosa L. Allesøe ◽  
Giacomo Oliveira ◽  
Shuqiang Li ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Epitope Spreading ◽  
Memory T Cell ◽  
Cell Responses ◽  
Persistent Memory

Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis

2006 ◽  
Vol 47 (2) ◽  
pp. 652 ◽  
Author(s):  
Cornelia A. Deeg ◽  
Barbara Amann ◽  
Albert J. Raith ◽  
Bernd Kaspers
Keyword(s):  
Epitope Spreading ◽  
Equine Recurrent Uveitis

Epitope spreading within lupus-associated ribonucleoprotein antigens

2005 ◽  
Vol 117 (2) ◽  
pp. 112-120 ◽  
Author(s):  
Umesh S. Deshmukh ◽  
Harini Bagavant ◽  
Janet Lewis ◽  
Felicia Gaskin ◽  
Shu Man Fu
Keyword(s):  
Epitope Spreading

scholarly journals Long-term suppression of EAE relapses by pharmacological impairment of epitope spreading

2014 ◽  
Vol 171 (6) ◽  
pp. 1501-1509 ◽  
Author(s):  
L Cavone ◽  
B Peruzzi ◽  
R Caporale ◽  
A Chiarugi
Keyword(s):  
Epitope Spreading

Generation of T-Cell Immunity to the HER-2/neu Protein After Active Immunization With HER-2/neu Peptide–Based Vaccines

2002 ◽  
Vol 20 (11) ◽  
pp. 2624-2632 ◽  
Author(s):  
Mary L. Disis ◽  
Theodore A. Gooley ◽  
Kristine Rinn ◽  
Donna Davis ◽  
Michael Piepkorn ◽  
...  
Keyword(s):  
T Cell ◽  
Stimulation Index ◽  
T Cell Immunity ◽  
Colony Stimulating Factor ◽  
Epitope Spreading ◽  
Cell Immunity ◽  
Her 2 ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

PURPOSE: The HER-2/neu protein is a nonmutated tumor antigen that is overexpressed in a variety of human malignancies, including breast and ovarian cancer. Many tumor antigens, such as MAGE and gp100, are self-proteins; therefore, effective vaccine strategies must circumvent tolerance. We hypothesized that immunizing patients with subdominant peptide epitopes derived from HER-2/neu, using an adjuvant known to recruit professional antigen-presenting cells, granulocyte-macrophage colony-stimulating factor, would result in the generation of T-cell immunity specific for the HER-2/neu protein. PATIENTS AND METHODS: Sixty-four patients with HER-2/neu–overexpressing breast, ovarian, or non–small-cell lung cancers were enrolled. Vaccines were composed of peptides derived from potential T-helper epitopes of the HER-2/neu protein admixed with granulocyte-macrophage colony-stimulating factor and administered intradermally. Peripheral-blood mononuclear cells were evaluated at baseline, before vaccination, and after vaccination for antigen-specific T-cell immunity. Immunologic response data are presented on the 38 subjects who completed six vaccinations. Toxicity data are presented on all 64 patients enrolled. RESULTS: Ninety-two percent of patients developed T-cell immunity to HER-2/neu peptides (stimulation index, 2.1 to 59) and 68% to a HER-2/neu protein domain (stimulation index range, 2 to 31). Epitope spreading was observed in 84% of patients and significantly correlated with the generation of a HER-2/neu protein–specific T-cell immunity (P = .03). At 1-year follow-up, immunity to the HER-2/neu protein persisted in 38% of patients. CONCLUSION: The majority of patients with HER-2/neu–overexpressing cancers can develop immunity to both HER-2/neu peptides and protein. In addition, the generation of protein-specific immunity, after peptide immunization, was associated with epitope spreading, reflecting the initiation of an endogenous immune response. Finally, immunity can persist after active immunizations have ended.

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