We develop and employ technologies at the intersection of genomics, proteomics, immunology, antibody engineering, and computational biology. We are generating a pipeline of new therapies for cancer patients in need as well as technologies to enable personalized immunotherapies. Resulting from these approaches, our novel class of peptide-centric (PC)-CAR T cells potently eradicate tumors in preclinical models and are entering clinical trials in 2024.

We study the genetics and biology of TCR and CAR gene modified T cells in vitro and in vivo in mouse and human systems. The focus of this talk will be to discuss how the marker gene we include in our vectors impacts on the final T cell products used for infusion into cancer patients and speculate why we don’t see serious adverse events in any of our patients post infusion. We will then discuss the future direction of our approach to make TCR and CAR transduced T cells work better for patient while remaining safe.

Heterogeneity in antigen expression and scarcity of targetable antigens limit the development of engineered cell therapies against many tumors. I will discuss a strategy of targeting tumors with weak/heterogenous expression of target antigens by selectively boosting anti-tumor cytotoxicity through an additional engineered receptor.

Tumor target antigen heterogeneity and similarity to normal cells require novel approaches to combinatorial CAR targeting. We utilize cooperative chimeric receptor design to efficiently eliminate tumor cells without increasing on-target/off-tumor toxicity. For acute myeloid leukemia (AML), we combine an attenuated ADGRE2-1XX-CAR with a CLEC12A-chimeric costimulatory receptor (ADCLEC.syn1) to preferentially engage ADGRE2^posCLEC12A^pos leukemic stem cells over ADGRE2^lowCLEC12A^neg normal hematopoietic stem/progenitor cells (HSPCs), following IF-BETTER logic-gating. ADCLEC.syn1 overcomes leukemic escape across clinically representative AML phenotypes, outperforms the ADGRE2-CAR alone, and eradicates AML despite proximate myelopoiesis in humanized mice. A clinical trial investigating ADCLEC.syn1 T cells in relapsed/refractory AML is upcoming (NCT05748197).

The limited efficacy of chimeric antigen receptor (CAR) T cell therapy for solid tumors necessitates engineering strategies that promote functional persistence in an immunosuppressive environment. CAR T cells with c-Kit D816V mutation (KITv) have upregulated STAT phosphorylation, antigen activation-dependent proliferation, and CD28- and interleukin-2-independent and interferon-γ-mediated co-stimulation-enhanced survival, including in transforming growth factor-ß-rich and low-antigen-expressing solid tumor models. KITv CAR T cells are susceptible to kinase inhibitors (safety switch).

Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer treatment, demonstrating remarkable efficacy in treating hematological malignancies. However, solid tumors present a more formidable challenge, often evading CAR T cell recognition and destruction. To overcome these limitations, researchers are exploring advanced engineering with multiplexed gene-editing, augmented manufacturing, as well as the integration of artificial intelligence into CAR T cell therapy, opening new avenues for efficacious treatment of solid tumors.

We are using EGFR-IL13Ra2 targeting bivalent CAR T cells to treat recurrent glioblastoma at the University of Pennsylvania. Cells are delivered loco-regionally to CSF via an Ommaya reservoir. We have observed early radiographic responses, along with robust and prolonged CSF engraftment of CAR T cells in CSF in all patients treated. Implications for development of CAR T cell therapeutics to glioblastoma and other CNS tumors will be discussed.

GPC2 is a new target in neuroblastoma. Anti-GPC2 CAR T-cells utilizing the CT3 mouse antibody control neuroblastoma tumors in mice. However, CAR T-cells are less effective against tumors with low antigen expression. Here, we utilize a gamma/delta T-cell receptor framework (called AbTCR) that contains CT3 or humanized CT3 (hCT3). We demonstrated that the hCT3 AbTCR is highly effective in reducing GPC2+ neuroblastoma tumors including low antigen density tumors.

Collectively, brain tumors are responsible for more deaths in children than any other cancer diagnosis. There is great interest in the application of CAR T cell strategies to solid tumors, however, doing so will require new approaches in CAR T cell design to make this therapy safe and effective. We have engineered CAR T cells that are restricted to recognize the unique combination of two distinct antigens identified in various types of pediatric brain tumors using logic-to-gate the function of CAR T cells. These CAR T cells showed specificity and increased efficacy in targeting tumor cells while protecting single antigen-expressing normal cells. 

To provide a means for quantitative control of CAR T cell activity, our team first created universal immune receptors (UniCARs), a versatile CAR-like platform for the denovo generation and quantitative control of tumor antigen-specific T cells where human T cells are genetically engineered with adaptable docking immune receptors and can be conferred with highly personalized tumorspecificity via pre-targeting with “tagged” antigen-specific small molecules, antibodies, scFvs or receptor ligands.

• What are design principles? 
• What are challenges? 
• What is impact of IgG subclass for Fc-fusion proteins? 
• How to profile multispecifics? 
• What are developability considerations and characterization​?

Adoptive cell therapy using CAR T cells have had limited success in patients with solid tumors. However, recent advances in the development of NK cell therapeutics could result in better outcome in patients. These include differences in the sources of NK cells to make the product, use of more potent antibodies to cell surface tumor antigens and engineering of NK cells to increasing their persistence and activity.

Immunosuppressive tumor microenvironment is a major barrier for advancing cellular immunotherapy including NK cell CARs. To overcome this barrier, we have developed mesothelin targeting NK cell CARs (MSLN-CAR NK cells) with novel IL-12 arming strategy. This allows us to deliver highly activating cytokine into the TME, leading to enhanced anti-tumor activity against multiple tumor types including ovarian and pancreatic cancer in vitro and in vivo.

CAR T cell therapy has demonstrated clinical efficacy against relapsed and refractory hematological malignancies. However, prominent barriers including poor T cell effector function, lack of proliferation, and limited CAR T cell persistence have prevented CAR T cell therapies from reaching their full curative potential, especially in solid tumors. This talk will present the innovative SYNCAR technology which leverages engineered IL-2/IL-2Rß orthogonal pairs to selectively enhance the anti-tumor efficacy of CAR T cells, addressing challenges faced in both liquid and solid tumor models.

Founded in 2019, BlueSphere Bio has developed innovative technologies for neoantigen and TCR discovery, aimed at advancing treatments for cancers with significant unmet needs, particularly in blood and solid tumors. The company now boasts a robust pipeline portfolio primarily focused on transformative TCR-based and advanced therapies, including TCR T cell therapies, T cell bispecific engagers, in vivo TCR T cell therapy, and cancer vaccines designed for combination treatments.

Cell therapies have revolutionized how we treat cancer; however, there remains an unmet need for improved treatment of solid tumors. Carisma is 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 presentation will discuss progress on CAR-M and CAR-Mono, including ex vivo cell therapy and in vivo reprogramming using mRNA.

Tumor-infiltrating lymphocytes (TIL) that recognize tumor antigens experience chronic antigen stimulation in the tumor microenvironment (TME) resulting in TIL dysfunction. Genetic modification of TIL can provide costimulation within the TME. CoStAR is a costimulatory antigen receptor consisting of an scFv-recognizing folate receptor alpha on tumor cells and CD28 and CD40 intracellular signaling domains. CoStAR improves TIL proliferation upon chronic antigen stimulation, and increases cytokine secretion and tumor lysis. CoStAR also improves T cell persistence and PFS in a mouse model. CoStAR amplifies TCR signaling without off-tumor T cell activation. A clinical trial investigating CoStAR in NSCLC patients is underway.