In addition to complications of acute diseases, chronic viral infections are linked to both malignancies and autoimmune disorders. Lack of adequate treatment options for Epstein-Barr virus (EBV), Human T-lymphotropic virus type 1 (HTLV-1), and human papillomavirus (HPV) remains. The NexImmune Artificial Immune Modulation (AIM) nanoparticle platform can be used to direct T cell responses by mimicking the dendritic cell function. In one application, AIM nanoparticles are used ex vivo to enrich and expand (E+E) rare populations of multi-antigen-specific CD8+ T cells for use of these cells as an AIM adoptive cell therapy. This study has demonstrated using E+E CD8+ T cells, the functional relevance of targeting EBV, HTLV-1, and HPV. Expanded T cells consist primarily of effector memory, central memory, and self-renewing stem-like memory T cells directed at selected viral antigen peptides presented by the AIM nanoparticle. T cells expanded against either EBV- or HPV-antigens were highly polyfunctional and displayed substantial in vitro cytotoxic activity against cell lines expressing the respective antigens. Our initial work was in the context of exploring T cells expanded from healthy donors and restricted to human leukocyte antigen (HLA)-A*02:01 serotype. AIM Adoptive Cell Therapies (ACT) are also being developed for other HLA class I serotypes. AIM adoptive cell therapies of autologous or allogeneic T cells specific to antigens associated with acute myeloid leukemia and multiple myeloma are currently in the clinic. The utility and flexibility of the AIM nanoparticle platform will be expanded as we advance the second application, an AIM injectable off-the-shelf nanoparticle, which targets multiple antigen-specific T cell populations to either activate, tolerize, or destroy these targeted CD8+ T cells directly in vivo, leaving non-target cells alone. The AIM injectable platform offers the potential to develop new multi-antigen specific therapies for treating infectious diseases, cancer, and autoimmune diseases.

No abstract

Background NexImmune is developing novel, antigen-specific immunotherapies to meet serious unmet clinical needs. Here we report on the development of adoptive cell therapies (ACT) for virally driven malignancies. The proprietary Artificial Immune Modulation (AIM™) platform mimics natural T cell biology to target, activate and expand antigen-specific CD8 + T cells. EBV, HPV, and HTLV are estimated to contribute to 6-7% of global cancer cases. The targeted antigens are implicated in multiple malignancies including B cell lymphomas (EBV), adult T cell leukemia/lymphoma (HLTV1) as well as multiple HPV related malignancies such as oropharyngeal, cervical, and anal cancers. Methods Using the paramagnetic AIM nanoparticle as an artificial antigen presenting cell (aAPC), in two-weeks T cells were enriched and expanded from HLA-A*02:01 donor apheresis material against immunodominant antigens of EBV, HTLV, and HPV. The memory phenotype of these cells was determined by CD45RA, CD62L, and CD95 expression. Antigen specific killing was observed on HLA-A2+ cell lines and polyfunctional activity characterized by an intracellular cytokine staining assay.Results Greater than 90% of the total resulting CD8 + T cells display a phenotype of effector, central, or long-lived stemlike memory. From 8 independent healthy donor clinical scale manufacturing runs of NEXI-003, a pentavalent specific AIM ACT against the E6 and E7 antigens of both HPV-16 and HPV-18, as well as the tumor-associated antigen Survivin, 0.28E9 to 3.79E9 cells were generated. These cells showed dual HPV-16 + and HPV-18 + cancer antigen specificity and cytotoxic activity against HLA-A2 + cell lines, without significant cytotoxic activity against autologous PBMCs. With respect to EBV, using HLA-A2 + cell lines we further show antigen specific killing directed at LMP2, BRLF1, BMLF1, EBNA3, and LMP1 from a single healthy donor AIM ACT selected on 6 EBV antigens. In addition, these expanded memory T cells demonstrate a high degree of polyfunctional activity upon stimulation. Conclusions NEXI-003 is an immunotherapy for HPV cancers in HLA*A02:01 patients that recently received IND clearance and it is anticipated to begin clinical trials in 2022. In addition to B cell lymphomas, B cells that are present in the plaques of multiple sclerosis patients have been found to express EBV antigens. Therefore, by directing a multivalent EBV T cell response there is the potential to treat other EBV-associated diseases using one AIM ACT product. Results reported here, will support the expansion of the AIM platform modalities for use in the treatment of virally driven malignancies, as well as potential virally associated autoimmune and infection diseases.