Chimeric antigen receptor (CAR) T cells have been shown to be an effective treatment option against B cell malignancies. Early in vitro characterization efforts have been largely manual and low-throughput. Using automated liquid handling and data analysis, we can now screen hundreds of unique CAR T cells; thereby allowing for the discovery of functionally relevant, lead binders and the assessment of structure-activity relationships among CAR components.

Effective cellular therapies for solid tumors have proved elusive. We present new platforms to rapidly assess the functional effects of large pools of T cell genetic modifications in parallel non-virally. Pooled knock-ins combined with single-cell sequencing also revealed high-dimensional cellular phenotypes associated with improved clearance of solid tumor xenografts. Scalable discovery and engineering of T cell therapies will enable more rapid clinical development of curative cell therapies for solid tumors.

Despite the success of high-potency oncology biologics in treating liquid tumors, they are limited as solid tumor therapeutics. Keyway TCR Discovery at Alloy Therapeutics discovers antibodies mimicking T cell receptors (TCRm) and TCRs engineered in high affinity and specificity to pHLA tumor antigens, so these new modalities can successfully treat solid tumors. Keyway embraces Alloy’s business strategy integrating related platforms, services, and venture studio new company creation focused on this modality. 

Cell and gene immunotherapies are revolutionizing how we treat disease, with multiple FDA-approved therapies that have transformed cancer treatments. However, advances in gene delivery, manufacturing, and therapeutic cargoes are still required to increase the impact and scope of these promising approaches. Our laboratory is working to develop approaches that improve the specificity of cellular engineering, and the potency of cells once engineered.

Effectively addressing cell-specific delivery has an opportunity to improve the therapeutic potential of in vivo gene therapies. We have developed a novel platform for engineering fusogens to target cellular molecules of choice, thereby enabling in vivo cell-specific delivery across many cell types with a fusogen-directed gene therapy vector. In vivo generation of CAR T cells, using gene therapy vectors with T cell targeting fusogens for in vivo CAR delivery, show promise in preclinical models and may provide for broader access to CAR therapies.

Fibrosis is seen in nearly every form of heart disease and is a significant factor in disease progression. Current treatments for fibrosis remain limited, necessitating new approaches. In a mouse model of heart disease, we were able to target and ablate activated cardiac fibroblasts in hearts will established fibrosis using Fibroblast Activation Protein (FAP) CAR T cells. This treatment significantly reduced cardiac fibrosis and rescued cardiac function. In addition, we were able to obtain similar results by generating FAP CAR T cells in vivo using non-viral delivery of FAPCAR mRNA to T cells. 

Adoptive cell therapies have demonstrated remarkable outcomes in hematologic malignancies, but efficacy in solid tumors is still lacking. We have established a novel, proprietary monocyte and macrophage based cell therapy platform based on chimeric antigen receptor macrophages (CAR-M). In this talk we will review the CAR-M platform, present novel preclinical data, and discuss the ongoing Phase I, first-in-human CAR-M trial for HER2+ metastatic solid tumors.

This presentation will briefly introduce the trends in cancer cell therapy based on the published data. It will mainly focus on Acro’s solutions to support cell gene therapy (CGT) at different stages from early drug discovery, manufacture /quality control to preclinical and clinical research. It will introduce Acro’s key products, new technology platform and new product pipeline including Star staining fluorescent conjugation and GMP grade products, etc.

Our first-in-human armored CAR targeting PSMA (with a 41BB and CD3 endodomain) coupled with a dominant-negative TGFBR2, showed anti-tumor effects but also significant toxicity from macrophage activation (MAS). We designed a CAR with additional armor (a PD1-CD28 switch) and compared the 41BB endodomain with a novel CD2 domain. Preliminary data indicated the CD2 based endodomain tricistronic CAR against PSMA maintained cytotoxicity, memory profile, and activation while having a significantly reduced risk of inducing macrophage activation.

Although CAR T cells have shown remarkable results against hematological malignancies, many aspects of this technology remain to be improved. Despite remarkable initial responses, relapses occur in a large proportion of patients with poor CAR T cell persistence or tumors expressing very low levels of target antigen. We are using pooled CRISPR KI to screen for novel CAR architectures with improved proliferation, persistence, or sensitivity against low antigen densities.

Ichnos’ BEAT® platform (Bispecific Engagement by Antibodies based on the TCR) facilitates design of multispecific antibodies using efficient heavy chain heterodimerization and a common light chain. ISB 1442, a first-in-class 2+1 biparatopic BEAT® 2.0 bispecific (CD38xCD47) antibody, demonstrates higher potency and tumor growth inhibition preclinically relative to daratumumab. A Phase 1 study in hematologic malignancies is planned for mid-2022.

Donor NK cells can induce complete remissions in patients with refractory leukemia. However, limitations include lack of persistence and specificity. Trispecific killer engagers (TriKE) that target endogenous NK cells or enhance cell products are in clinical development. Off-the-shelf NK cells from induced pluripotent stem cells containing multiple gene edits will promote specificity, persistence, and enhanced activity in vivo to enhance cancer therapy.

Cell Squeeze technology enables precise cell engineering while preserving cell health and function. Our lead program, engineered APCs, has demonstrated safety and stimulation of immune responses in certain patients with HPV16+ tumors. Other platforms include activating antigen carriers (AACs), and tolerizing antigen carriers (TACs) manufactured from RBCs for antigen-specific activation or suppression respectively. Currently, billions of cells can be processed per minute and personalized therapies are manufactured in <24hrs.

Natural Killer (NK) cells are innate immune cells that can eliminate target cells in an antigen-independent fashion. NK cells can be engineered to express chimeric antigen receptors (CARs), expanded under different conditions, and gene edited to further enhance cytotoxicity, selectivity, and persistence. Nkarta is developing off-the-shelf CAR NK cells to maximize the therapeutic potential of allogeneic NK cells alone or in combination with other agents.