This presentation will commence with an update on a clinical trial using a panErbB-targeted second-generation CAR known as T4 immunotherapy. I will present preclinical data generated using two next-generation CAR T cell platforms: dubbed parallel CAR and adaptor CAR.

During the development of our clonal neoantigen T cell therapy (cNeT) for treatment of solid tumours, we identified and screened circa 10,000 clonal neoantigens for T cell reactivity using cells grown from tumour infiltrating lymphocytes. Using this unique data, we developed and validated an AI method for predicting neoantigen immunogenicity, significantly outperforming existing tools. This technology has broad applicability for optimising target selection across all types of personalised neoantigen therapies.

Cell therapies have revolutionized how we treat cancer; however, there remains an unmet need for improved treatment of solid tumors. Carisma is dedicated to developing a differentiated cell therapy platform focused on engineered macrophages, cells that play a crucial role in both the innate and adaptive immune response. The first applications of the platform, are CAR-macrophages for the treatment of solid tumors and have the potential to transform the treatment of cancer and other serious illnesses. We will present data from our ongoing Phase 1 study of an anti-HER2 CAR-Macrophage and discuss next steps for our platform and programs.

The goal is to develop a next generation CAR T cell therapy for solid tumor by addressing limitations of current CAR T cell therapy: limited T cell trafficking, persistence, and the immunosuppressive tumor microenvironment. We have developed nucleotide metabolic reprogrammed CAR T cells (designated as MR-CAR-T) by arming with CD26 and ADA. CD26 induces a rich chemokine receptor profile, enabling CAR T cells to traffic to solid tumors, while ADA irreversibly converts adenosine (an immunosuppressive metabolite) to inosine that can support CAR T cell growth and function in the absence of glucose.

Despite the remarkable clinical activity of CAR T cells in B-ALL, 50% of the patients experience relapse. Antigen loss or downregulation of the target antigen is the most common mechanism of relapse. CARs are inefficient at recruiting proximal signaling molecules when antigen density is limiting. We engineered a novel platform that significantly amplifies CAR T cell signaling and activation, providing a resource to overcome antigen heterogeneity and resistance through downregulation.

MiNK Therapeutics uses invariant Natural Killer T (iNKT) cells to develop allogeneic cell therapy for patients with solid tumours. iNKT cells directly counteract immune suppression by myeloid cells and have a profound impact on the tumor micro-environment. We have developed an allogeneic armoured CAR-iNKT product targeting Fibroblast Activation Protein (FAP) and secreting interleukin 15 to further enhance the natural anti-cancer properties of iNKT cells. FAP CAR-iNKT selectively kills FAP-positive Cancer-Associated Fibroblasts, which directly impacts tumor growth and strongly potentiates an anti-cancer cytotoxic T cell response, leading to durable complete response in a murine disseminated lung cancer model. 

To prevent CD19 antigen escape in B-cell malignancies, we screened CD19/NKG2DL dual CAR constructs. In vitro, T cells transduced with these constructs displayed cytotoxic activity, proliferated, and secreted cytokines in presence of WT and CD19 KO B-ALL cancer cells. Since NKG2DL are expressed in many cancer indications and absent from healthy tissues, use of NKG2DL-based dual CAR T cells is an attractive approach to improve anti-tumor efficacy in solid indications.

Recent advances in CRISPR/Cas9 gene editing for primary T lymphocytes have presented new avenues for the precise engineering of armoured CAR T cells.  In this study we engineered CAR T cells using CRISPR HDR to express cytokines under the transcriptional control of tumour-specific promoters, and hypothesised that this would enhance the safety and efficacy of armoured CAR T cells. The results demonstrated simultaneous deletion of inhibitory genes while achieving tumour-specific control of cytokine expression by gene-edited CAR T cells. This approach enhanced both tumour cytotoxicity and anti-tumour efficacy in vivo in the absence of toxicity.

In this study, two highly enriched TCR clonotypes that contain TRDV segments in their TCR alpha chains were identified. Transfection of both TCRs showed cell surface localization and tumor recognition of the human, TRDV1-containing TCR could be demonstrated by IFN gamma ELISpot. TRDV-containing TCRs were found to contribute significantly to TCR alpha diversity. We suggest examining all_contig_annotations files of 10x VDJ sequencing for TRDV-containing alpha chains in solitary beta chains.

Sakura bio developed a novel and effective technology for expansion and activation of PBMC’s derived cytotoxic CD8+ T cells from healthy donors. Comprehensive preclinical studies validated the killing superiority of SAK vs. other T-cell-based therapies (including cytokine-induced killer cells (CIK)) in different tumor models (in vitro and in vivo). SAK’s outstanding killing properties of leukemic cells lead Sakura bio to choose Acute Myeloid Leukemia (AML) as its first-in-man indication.

• ​Features of the TME which are hostile to CAR T cell efficacy
• Strategies for engineering CARs to address the solid tumour TME hurdles
• Combination treatments with novel CARs —chemotherapy, radiotherapy, oncolytic virus
  

• Cell therapy and immuno-oncology combinations
• The role of checkpoint inhibition as combination partner
• Co-stimulation as emerging modality​
• How to boost a secondary immune response?​
  

T cells engineered to express TCRs against shared HPV-driven tumor-specific antigens are a promising treatment option for patients with metastatic and refractory epithelial cancers. Objective response rates as high as 50% have been observed. However, durable responses are still elusive. Recent translational data point to various mechanisms of treatment resistance employed by the tumor in context of TCR-engineered T cell therapy.

We studied the impact of combining a TCR with a switch receptor (PD1-41BB) on the control of tumor growth in vivo targeting a cancer-testis antigen. These studies demonstrated that provision of integrated co-stimulation through the switch receptor imbues TCR T cells with capacities that cannot be achieved with TCR T cells expressing the naked TCR alone and provides strong enhancement of clinical efficacy as assessed in a preclinical in vivo xenograft model of tumor control, whereby tumor cells express high levels of PD-L1 that normally greatly hinder TCR T function.

We have developed a high-precision, cell-based platform for the development of TCRs for therapeutic use. The platform uses engineered cells to recapitulate HLA-allele-specific processing and presentation of antigens, as well as TCR-mediated functional response. A number of formats of the cells are combined to build systematic workflows for identification, isolation, validation, de-risking, and engineering of clinical candidates.

• ​Production of tumor-infiltrating lymphocytes (TILs) from melanoma according to GMP
• Randomized Phase 3 clinical trial to assess the effect of TIL therapy compared to standard immune checkpoint inhibition therapy with ipilimumab
• From an academic ATMP toward marketing authorization​

Pan Cancer T is progressing a pipeline of T cell receptor (TCR) therapeutics directed against untapped targets across 10 solid cancers. Our lead program, PCT-1, is specific for a highly homogenous target expressed by >80% of triple negative breast cancer patients amongst other tumors. We also develop next- generation technologies, aiming to enhance the durability of responses within the hostile tumor microenvironment, which should be broadly applicable to TCR-T therapies.