Research
Antibody-based immunotherapies represent one of the most promising approaches in the fight against human malignancies. By combining the precision of tumor antigen recognition through antibody variable domains (heavy and light chains) with the potent cytotoxicity of T cells, therapies like chimeric antigen receptor (CAR) T cells and T cell engagers have demonstrated remarkable success in specifically targeting and destroying cancer cells. However, many tumors inevitably relapse over time due to challenges such as antigen loss, mutation, or low cell surface density. While targeting multiple antigens simultaneously offers a potential solution to these issues, traditional single-chain variable fragments (scFvs) often face technical challenges, including cross-pairing, aggregation of CAR constructs, or difficulties in assembling large, complex antibody structures.
In the Casellas Laboratory, we aim to overcome these barriers by leveraging the unique properties of single-chain antibodies, also known as nanobodies. Derived from camelid immune systems, nanobodies are small, highly stable, and structurally simple, making them an ideal platform for the development of next-generation immunotherapies. By combining alpaca immunizations with large-scale human nanobody phage library screening, we have established a robust high-throughput pipeline to rapidly isolate highly specific nanobodies against diverse tumor antigens.
Our current projects focus on the design and implementation of multimeric CAR T cells targeting both extracellular and intracellular antigens, including peptide-HLA complexes, in hematopoietic and solid tumors. These multimeric CARs allow simultaneous recognition of multiple tumor-specific targets, reducing the risk of relapse due to antigen escape. Through innovation in nanobody engineering and structural information, we are also addressing challenges related to tumor heterogeneity and low antigen density. With an emphasis on precision, scalability, and clinical applicability, our work represents a significant step forward in the development of transformative therapies for cancer patients.