He and colleagues developed a transient, non-gene-editing platform for off-the-shelf allogeneic TCR-T therapy. By conferring tacrolimus resistance characteristics to IL-2/4/7 expanded TCR-T cells that display reduced alloreactivity, He et al. provided a proof-of-concept for an allogeneic TCR-T therapy approach that addresses both manufacturability, and unwanted graft and host alloreactivity concerns.

Todo and colleagues describe the development of IL-12-expressing oncolytic HSV-1 derived from the clinically validated G47Δ platform for malignant melanoma. Intratumoral treatment controls both injected and distant tumors and shows enhanced efficacy with PD-1 blockade. Favorable preclinical safety supports clinical translation and has enabled the ongoing investigator-initiated clinical trial.

In 2012, I had the distinct honor of being part of one of the trailblazing teams leading first-in-human/first-in-child chimeric antigen receptor (CAR) T cell trials in B cell acute lymphoblastic leukemia (B-ALL). Little did I know then that we were only at the tip of the iceberg for use of immunotherapy in pediatric oncology. While the multiple CAR T cell approvals for B cell malignancies, including in pediatric B-ALL, reflect the curative potential in relapsed/refractory disease, what has additionally transpired is a cascade of novel immune-effector cell therapy-based approaches, each iteratively building upon the prior to further extend the therapeutic index of immunotherapy.

Nguyen and colleagues engineered bispecific TCEs targeting p53R273H neoantigens presented by HLA-C*01:02. Machine learning-guided optimization (Boltz-2/EvotProGrad) yielded TCE01Cr3 (Kd = 2.51 nM), a small, high-affinity, specific TCE with mouse serum stability (t1/2 ≈ 40 h), and monotherapy efficacy (> 80% tumor elimination in 3D models) without off-target toxicity or chemotherapy.