AIM Platform: A Novel Nano Artificial Antigen-Presenting Cell-Based Clinical System Designed to Consistently Produce Multi-Antigen-Specific T-Cell Products with Potent and Durable Anti-Tumor Properties

Abstract

Over the last decade, tremendous progress has been made in the field of adoptive cell therapy. The two prevailing modalities include endogenous non-engineered approaches and genetically engineered T-cell approaches. Endogenous non-engineered approaches include dendritic cell-based systems and tumor-infiltrating lymphocytes (TIL) that are used to produce multi-antigen-specific T-cell products. Genetically engineered approaches, such as T-cell receptor engineered cells and chimeric antigen receptor T cells are used to produce single antigen-specific T-cell products. It is noted by the authors that there are alternative methods to sort for antigen-specific T cells such as peptide multimer sorting or cytokine secretion assay-based sorting, both of which are potentially challenging for broad development and commercialization. In this review, we are focusing on a novel nanoparticle technology that generates a non-engineered product from the endogenous T-cell repertoire. The most common approaches for ex vivo activation and expansion of endogenous, non-genetically engineered cell therapy products rely on dendritic cell-based systems or IL-2 expanded TIL. Hurdles remain in developing efficient, consistent, controlled processes; thus, these processes still have limited access to broad patient populations. Here, we describe a novel approach to produce cellular therapies at clinical scale, using proprietary nanoparticles combined with a proprietary manufacturing process to enrich and expand antigen-specific CD8⁺ T-cell products with consistent purity, identity, and composition required for effective and durable anti-tumor response.

Keywords: Acute myeloid leukemia; Adoptive cell therapy; Artificial antigen-presenting cell; CD8; Clinical trial; Dendritic cells; GMP; Human; Multiple myeloma; Nano, nanoparticle; Prodigy, CliniMACS; T cells, T-cell manufacturing.

Fig. 1

AIM-np consist of a superparamagnetic iron-oxide nanoparticle, to which humanized HLA-A2-IgG4 hinge dimer (signal 1) and humanized anti-CD28 antibody (signal 2) molecules are covalently linked. AIM-np can be loaded with an HLA-A*02:01-restricted peptide of choice (shown in green) and lead to the activation and proliferation of antigen-specific CD8⁺ T cells. aAPC, artificial antigen-presenting cell.

Fig. 2

Enrichment and Expansion of antigen-specific CD8⁺ T cells. Leukapheresis material is collected from human donors and put into a CliniMacs-Prodigy® cell expansion system (Miltenyi Biotec). Magnetic separation is used to deplete CD4⁺ T cells and to enrich for antigen-specific CD8⁺ T cells using the AIM-np. The enriched cell suspension is placed in G-Rex expansion flasks in combination with a proprietary cytokine mix. Cultures are expanded for 2 weeks. Using this process allows for the consistent generation of clinically relevant numbers of antigen-specific CD8⁺ T cells (shown as blue cells). Portions of cartoon adapted from Perica et al. [6].

Fig. 3

Characteristics of AML T cells produced by Enrichment and Expansion process using peptide cocktail derived from WT1, PRAME, and cyclin A1. A Our manufacturing process produces a T-cell product at therapeutically relevant cell numbers. B Total antigen specificity (n = 4) is upwards of 20%. L52, L55, L80, and L92 refer to individual leukopak experiments (A and B). The T cells in the final product are polyfunctional and display multiple effector functions upon non-specific stimulation (C and D).

Fig. 4

The representative data shows over 95% cells in our final T-cell product are memory phenotype. A A representative breakdown of memory subtypes defined by CD62L and CD45RA as indicated in the dot plot. T naïve cells and T_scm cells are further distinguished by CD95 expression as shown in the histograms. The histogram is an analysis of the CD62L⁺, CD45RA⁺ cells. B Overview of memory subtype distribution across 4 products. T stem cell memory (T_scm), T central memory (T_cm), T effector memory (T_em), and T effector memory CD45RA positive (TEMRA).