Lymph node targeted multi-epitope subunit vaccine promotes effective immunity to EBV in HLA-expressing mice

Dasari, Vijayendra; McNeil, Lisa K.; Beckett, Kirrilee; Solomon, Matthew D.; Ambalathingal, George; Thuy, T. Le; Panikkar, Archana; Smith, C.; Steinbuck, Martin P.; Jakubowski, Aniela; Seenappa, Lochana; Palmer, Erica; Zhang, Jeff; Haqq, Christopher M.; DeMuth, Peter C.; Khanna, Rajiv

doi:10.1038/s41467-023-39770-1

Cited by 10 publications

(5 citation statements)

References 78 publications

(93 reference statements)

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“…Next, to explore anticancer activity of anti-CD19 autologous CAR T and allogeneic CAR NK cells in vivo, we implanted lymphoblastoid tumor cells (LCL) subcutaneously into NSG mice [ 35 – 37 ], modeling human B cell lymphoma therapy with either autologous CAR T cells [ 38 ] or allogeneic CAR NK cells [ 11 ]. Mice were treated with adoptive cell transfer (ACT) three days after tumor engraftment and injection of IL-2 to support transferred cells.…”

Section: Resultsmentioning

confidence: 99%

CAR T cells outperform CAR NK cells in CAR-mediated effector functions in head-to-head comparison

Egli,

Kaulfuss,

Mietz

et al. 2024

Exp Hematol Oncol

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Background CAR NK cells as vehicles for engineered “off-the-shelf” cellular cancer immunotherapy have attracted significant interest. Nonetheless, a comprehensive comparative assessment of the anticancer activity of CAR T cells and CAR NK cells carrying approved benchmark anti-CD19 CAR constructs is missing. Here, we report a direct head-to-head comparison of CD19-directed human T and NK cells. Methods We generated CAR T and CAR NK cells derived from healthy donor PBMC by retroviral transduction with the same benchmark second-generation anti-CD19 CAR construct, FMC63.28z. We investigated IFN-γ secretion and direct cytotoxicity in vitro against various CD19+ cancer cell lines as well as in autologous versus allogeneic settings. Furthermore, we have assessed anticancer activity of CAR T and CAR NK cells in vivo using a xenograft lymphoma model in an autologous versus allogeneic setting and a leukemia model. Results Our main findings are a drastically reduced capacity for CAR-mediated IFN-γ production and lower CAR-mediated cytotoxicity of CAR NK cells relative to CAR T cells in vitro. Consistent with these in vitro findings, we report superior anticancer activity of autologous CAR T cells compared with allogeneic CAR NK cells in vivo. Conclusions CAR T cells had significantly higher CAR-mediated effector functions than CAR NK cells in vitro against several cancer cell lines and autologous CAR T cells outperformed allogeneic CAR NK cells both in vitro and in vivo. CAR NK cells will likely benefit from further engineering to enhance anticancer activity to ultimately fulfill the promise of an effective off-the-shelf product.

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Section: Resultsmentioning

confidence: 99%

CAR T cells outperform CAR NK cells in CAR-mediated effector functions in head-to-head comparison

Egli,

Kaulfuss,

Mietz

et al. 2024

Exp Hematol Oncol

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“…For example, multi-epitope vaccines targeting Epstein–Barr virus (EBV) and influenza virus successfully elicit robust neutralizing antibodies and T-cell responses. The EBV polyepitope vaccine, which includes 20 CD8 + T-cell epitopes, induces high frequencies of CD4 + T cells and CD8 + T cells, which are maintained for more than 7 months ( Dasari et al, 2023 ). It has been reported that the norovirus (NoV) P particle, a 24-self-assembly of the protruding domain, displays H16, M2e, and NP9 on its surface, which elicit long-lasting hemagglutinin (HA)-specific neutralizing antibodies, M2e-CD4 + and CD8 + T-cell responses, and a nucleoprotein-specific CTL response, respectively ( Nie et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Multi-epitope vaccine design for hepatitis E virus based on protein ORF2 and ORF3

Lu,

Wu,

Meng

et al. 2024

Front. Microbiol.

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IntroductionHepatitis E virus (HEV), with heightened virulence in immunocompromised individuals and pregnant women, is a pervasive threat in developing countries. A globaly available vaccine against HEV is currently lacking.MethodsWe designed a multi-epitope vaccine based on protein ORF2 and ORF3 of HEV using immunoinformatics.ResultsThe vaccine comprised 23 nontoxic, nonallergenic, soluble peptides. The stability of the docked peptide vaccine-TLR3 complex was validated by molecular dynamic simulations. The induction of effective cellular and humoral immune responses by the multi-peptide vaccine was verified by simulated immunization.DiscussionThese findings provide a foundation for future HEV vaccine studies.

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“…Finally, EBV vaccination to stimulate endogenous TCRs has been advocated as a means to boost CAR armored EBVST expansion and function in patients ( 41, 42 ). This approach has been bolstered by recent strides in EBV vaccine delivery that have enabled effective and durable induction of EBV-specific T-cell responses ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

B7-H3–Targeting Chimeric Antigen Receptors Epstein-Barr Virus–specific T Cells Provides a Tumor Agnostic Off-The-Shelf Therapy Against B7-H3–positive Solid Tumors

Yeo,

Kua,

Tan

et al. 2024

Cancer Research Communications

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Encouraged by our observations of pronounced B7-H3 protein over-expression in many human solid tumors compared to healthy tissues, we focused on targeting B7-H3 with CAR T cells. We utilized a nanobody as the t B7-H3 targeting domain in our CAR construct to circumvent the stability issues associated with scFv-based domains. In efforts to expand patient access to CAR T cell therapy, we engineered our nanobody-based CAR into human Epstein-Barr Virus Specific T Cells (EBVSTs), offering a readily available off-the-shelf treatment. B7H3.CAR-armored EBVSTs demonstrated potent in vitro and in vivo activities against multiple B7-H3-positive human tumor cell lines and patient-derived xenograft models. Murine T cells expressing a murine equivalent of our B7H3.CAR exhibited no life-threatening toxicities in immunocompetent mice bearing syngeneic tumors. Further in vitro evaluation revealed that while human T, B and NK cells were unaffected by B7H3.CAR EBVSTs, monocytes were targeted due to upregulation of B7-H3. Such targeting of myeloid cells, which are key mediators of cytokine release syndrome (CRS), contributed to a low incidence of CRS in humanized mice after B7H3.CAR EBVST treatment. Notably, we showed that B7H3.CAR EBVSTs can target B7-H3 expressing myeloid-derived suppressor cells (MDSCs), thereby mitigating MDSC-driven immune suppression. In summary, our data demonstrate that our nanobody-based B7H3.CAR EBVSTs are effective as an off-the-shelf therapy for B7-H3 positive solid tumors. These cells also offer an avenue to modulate the immunosuppressive tumor microenvironment, highlighting their promising clinical potential in targeting solid tumors.

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Lymph node targeted multi-epitope subunit vaccine promotes effective immunity to EBV in HLA-expressing mice

Cited by 10 publications

References 78 publications

CAR T cells outperform CAR NK cells in CAR-mediated effector functions in head-to-head comparison

CAR T cells outperform CAR NK cells in CAR-mediated effector functions in head-to-head comparison

Multi-epitope vaccine design for hepatitis E virus based on protein ORF2 and ORF3

B7-H3–Targeting Chimeric Antigen Receptors Epstein-Barr Virus–specific T Cells Provides a Tumor Agnostic Off-The-Shelf Therapy Against B7-H3–positive Solid Tumors

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