Volume 4 Issue 4, April 2023

Clinical utility of T cell engagers (TCEs) in cancer immunotherapy for solid tumors is hampered by on-target off-tumor activity and dose-limiting adverse events. A study now proposes a solution to tackle these challenges through the design and preclinical characterization of extended half-life TCEs that are conditionally activated in the tumor microenvironment.

As we age, organs undergo architectural and functional changes that deeply affect the fate of disseminated tumor cells (DTCs). A study now adds further complexity to this picture by revealing a role for the age-induced, fibrosis-associated factor PDGF-C in enabling ER⁺ DTCs to reawaken in aging lungs and thrive as overt metastasis.

The response rates of pediatric cancers to immune checkpoint inhibitor therapies are disappointingly low, particularly when compared to the remarkable impact of these drugs in many adult cancers. A new study leverages clinical trial data to identify biomarkers that might improve patient selection in future clinical trials.

The lack of tumor-specific surface antigens has limited the application of CAR T cells in solid tumors. A new AND-gated CAR T cell system repurposes proximal T cell signaling proteins to restrict activation to dual antigen encounter, mitigating on-target, off-tumor toxicity while preserving antitumor efficacy in preclinical models.

A study of the immune microenvironment of estrogen receptor-positive (ER⁺) invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) identifies pro-tumor and anti-tumor macrophages as key players that can potentially influence disease outcome.

Lobular breast cancer is the second most prevalent breast cancer subtype, but clinical trials have not focused on these patients. The GELATO study reveals the feasibility of trials that are specific for this difficult to treat cancer and indicates that patients with lobular breast cancer can benefit from immunotherapy using PD-L1 blockade.

Saur and colleagues provide an overview of single-cell analyses in pancreatic cancer and discuss their implications for our understanding of heterogeneity and plasticity in the tumor and its microenvironment.

Turrell et al. show that, in young mice, low-level PDGF-C expression maintains dormancy of disseminated tumor cells, but, in aged or fibrotic lungs, the PDGF-C-high environment promotes proliferation, which can be counteracted with inhibition of PDGFRα or PDGF-C blockade.

Schellenberger and colleagues engineer masked, conditionally active T-cell engagers targeting tumor antigens and CD3 and show potent, protease-dependent antitumor activity in mouse models, as well as safety in non-human primates.

Nabbi et. al. analyze immunohistochemistry, comprehensive genomic profiling, RNA-sequencing, and TCR-sequencing data from 66 pediatric patients with cancer from a phase 1–2 clinical trial (iMATRIX-atezo) to nominate biomarkers associated with response to immunotherapy in pediatric cancer.

Using single-cell and high-dimensional profiling of the immune microenvironment, Vignali and colleagues uncover distinct cell subsets and interactions in human invasive ductal and lobular breast carcinoma, with potential prognostic and therapeutic relevance.

Voorwerk et al. report the clinical and translational results from a phase II trial evaluating the combination of carboplatin with anti-PD-L1 in patients with invasive lobular breast cancer, who have been underrepresented in clinical trials so far.

Getz and colleagues demonstrate a computational approach to estimate the timing of genomic drivers in early tumor progression from cancer types that do not have premalignant disease, using HPV-negative and HPV-positive head and neck squamous cell carcinoma as examples.

Su et al. find that BACH1 specifically interacts with the p53 (R175H) hotspot mutant. This has double oncogenic effects, leading to increased expression of the pro-metastatic targets of BACH1 as well as blockage of its capacity to activate ferroptosis.