Since 2004, we have known that proteasomes can ligate peptide fragments through a process called peptide splicing, though few examples of their immunogenicity in the context of cancer have been published. We developed several pipelines to identify and predict these unconventional epitopes and tested their immunogenicity and potential for therapeutical applications mediated by CD8+ T cell cytotoxic activity.

TCR T cell therapy is an emerging therapeutic modality for the treatment of solid malignancies. Despite promising signs of clinical efficacy, the therapeutic potential of TCR T cells is limited by the risk of cross-reactivity to healthy tissues, which has previously resulted in severe toxicity. Here we report the removal of TCR cross-reactivity to specific off-targets using TCR-Engine, a high-throughput protein engineering method leveraging CRISPR-targeted TCR mammalian display, functional screening, and deep sequencing.

This study highlights the importance of improving aßT cell infiltration for aßT cell therapies and argues for the potential of CCR5 overexpression in CD8+ aßT cells for improving clinical outcomes, particularly in the treatment of solid malignancies.

Several clinical trials are currently evaluating adoptive cell transfer efficacy in combination with immune-checkpoint (IC) blockade. However, critical issues related to this combination is the occurrence of immune-related adverse events. The infusion of tumor-specific T-cells genetically inactivated for IC-expression offers an alternative strategy to this combotherapy. Here, we compared the impact of PD-1 or TIGIT deletion, main IC with connected inhibition pathways, in terms of T-cell fitness and anti-tumor functions.

Alaya.bio develops targeting polymeric nanoparticles that can be used either ex vivo or in vivo for efficient and stable transduction of quiescent cells (like T cells) while preserving their naive and memory phenotypes. This new generation of polymeric nanoparticle is actually evaluated for in vivo CAR T therapy applications.

Until now Chimeric Antigen Receptor CAR T cell (CAR-Ts) have not been successful in myeloid malignancies, such as acute myeloid leukemia (AML). The lack of robust activity is partially due to suboptimal AML antigen selection and to biologic characteristics of the leukemic stem cells (LSCs). Specifically, the BM niche, where LSCs reside, is involved in leukemia-promoting activity whilst suppressing normal hematopoiesis. Thus, eradicating LSCs within the niche is the ultimate challenge. Armoring CAR-Ts in order to drive them preferentially to the BM niche and consequently target the AML LSCs at their location may enhance the potency  of the conventional CAR-Ts.

Major limitations in the CAR field include the poor controllability of CAR T cells after administration in vivo and their limited tumor specificity. In this talk, I will present novel protein engineering strategies for CAR binding domains with improved tumor specificity, as well as engineered protein switches that allow for functional control of CAR T cells with orally available small molecule drugs.

LEU011 consists of autologous T cells engineered to co-express an NKG2D-targeted adaptor CAR and CXCR2 chemokine receptor. Immunotherapy with LEU011 has achieved compelling efficacy in a broad range of solid tumour models, encompassing both immortalised xenografts and PDX. Leucid Bio has recently secured regulatory approval to undertake a Phase 1 clinical trial in which LEU011 will be evaluated in patients with a range of NKG2D ligand solid tumours. An update on the LEU011 programme will be provided.

Cell therapies have revolutionized how we treat cancer; however, there remains an unmet need for improved treatment of solid tumours. 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 tumours 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.

Glioblastoma is the most common type of primary brain tumours with a high mortality rate, and the existence of blood-brain barrier (BBB) has impeded the efficient delivery of promising therapeutics, including CAR-T cells, into the brain to treat glioblastoma. Given the native ability of neutrophils to cross BBB, we tested the therapeutic concept that neutrophils could be engineered with synthetic CARs to target glioblastoma and effectively deliver chemo-drugs to cross BBB as a novel dual chemoimmunotherapy. Our results established that CAR neutrophil-mediated drug delivery may provide an effective and universal strategy for specific targeting of solid tumours.

The possibility to combine checkpoint inhibitors with TIL-based adoptive cell therapy is an appealing therapeutic approach. Preclinical models demonstrate that CPIs can benefit the phenotype of TILs and clinical trials have suggested a potential benefit. Furthermore, overexpression of PD-1 and LAG-3 on in vitro-expanded TILs indicates that blockade could be a relevant combination strategy to prevent TIL inactivation in vivo.

Tumour infiltration lymphocytes (TILs) therapy showed a great result in some types of cancers such as melanoma. Yet, it is not the case in other solid cancers and is more challenging. Therefore, a next-generation TILs is needed where the TILs become more functional with the help of neoantigen discovery. 

• How can we pick the best antigens for targeting?
• How many antigens and in which sequence do we need?
• What would the properties of ideal adaptors or modules for cell therapy look like?
• Will targeting be enough?
  

• Logic gated CAR T cells
• Small molecule-regulated switches to control CAR T cell function
• Improving efficacy, while maintaining safety
  

Expanding the clinical success of adoptive cell therapy to solid tumours is challenging. Promising efficacy has been observed with engineered T cell receptor (TCR) therapies; however, a significant need to improve remains. For TCR T therapies to be successful in inducing deep and durable clinical responses in solid tumours, a specific, sensitive, and safe (3S) TCR, armored, and enhanced to overcome the immunosuppressive tumor microenvironment, and utilising a manufacturing process generating an optimal drug product, is required. Here we discuss data from MDG1015 (NY-ESO-1/LAGE-1a), a third-generation, targeted TCR T therapy co-expressing a 3S TCR and PD1-41BB costimulatory switch protein.

A major barrier to cellular therapies in oncology is the adequate choice of antigen. In the absence of truly specific cancer surface antigens, targeting remains a trade-off between efficacy and toxicity. At the same time, cancer is heterogeneous and prone to downregulate antigens, driving therapeutic pressure. This talk will be dedicated to modular cell therapies that use antibody derivatives both as flexible targeting modality and safety control module.

The ability of interleukin-2 to strongly stimulate effector T cells has promoted its approval as the first cancer immunotherapy. Although it showed promising results in some patients, it caused dose-dependent side effects that hampered its use. Thirty years later, numerous improved IL-2- based biologics are entering clinical testing. We have generated a unique anti-IL-2 antibody that can bind IL-2 in a distinct way and direct its action to desired immune cells. Subsequently, using a novel cytokine-CDR grafting approach, we have developed a second-generation, single-molecule, biased-IL-2 construct with potent anti-tumour efficacy in preclinical models of advanced malignancies.