Selected Articles from This Issue

Results from the phase II CAPTIVATE study demonstrated that first-line treatment with fixed-duration ibrutinib plus venetoclax provides deep, durable responses and sustained progression-free survival with a favorable safety profile in young, fit patients with chronic lymphocytic leukemia. In the current analysis, Jain and colleagues show that no resistance-associated mutations in BTK, PLCG2, or BCL2 were identified in samples from patients experiencing progressive disease after completion of fixed-duration ibrutinib plus venetoclax. Clinical data for retreatment after progressive disease support the clinical relevance of these findings. These results suggest that fixed-duration combination treatment with ibrutinib plus venetoclax may mitigate the development of resistance mechanisms associated with continuous single-agent targeted therapies and allow for effective retreatment with ibrutinib or ibrutinib plus venetoclax, thereby extending clinical benefit with these agents.

Cachexia is common in patients with advanced cancer and is associated with poor outcomes. Currently, there are no agents approved by the U.S. Food and Drug Administration for treatment of cachexia. Serum growth differentiation factor 15 (GDF-15) has emerged as a promising endogenous regulator of the pathways mediating cachexia. Crawford and colleagues demonstrate that—in participants with advanced cancer, cachexia, and elevated GDF-15 serum concentration—subcutaneous administration of 200 mg ponsegromab (a monoclonal antibody against GDF-15) every 3 weeks (5 doses total) was well tolerated and suppressed serum unbound GDF-15 concentrations over the course of the treatment period. Increases in body weight of approximately 6.6% (relative to baseline) was observed at week 12. Other exploratory measures of efficacy demonstrated increased appetite and physical activity among participants. Overall, these findings highlight the role of elevated GDF-15 concentrations in cancer cachexia and support the continued development of ponsegromab for the treatment of cachexia.

Ali and colleagues performed single-cell transcriptomics and TCR clonotype tracking in paired blood and tumor samples from patients with resectable pancreatic ductal adenocarcinoma who received neoadjuvant chemoradiation with or without PD-1 blockade in the context of a phase II trial. PD-1 blockade induces CD8 T cell expansion in the blood, and some of these T-cell clonotypes are also found in the tumor, suggesting tumor-specificity. These results suggest that PDAC elicits an endogenous T-cell response that is amenable to reinvigoration by PD-1 blockade; however, the reinvigorated T cells show a signature of NF-κB signaling that is associated with poor response. In patients with PDAC, PD-1 blockade with chemoradiation, compared to chemoradiation alone, leads to improved tumor-specific T-cell responses observable in peripheral blood but does not elicit a fully protective signature in the reinvigorated T cells.

Emerging immunotherapies have shown great promise for the treatment of primary cancers but have yet to be fully applied to metastatic disease, which accounts for 90% of cancer deaths. Patients with brain metastases (BM) have a median survival time of 4-12 months after diagnosis because the current standard of care is palliative, highlighting the need for novel targeted therapies. Here, Kieliszek and colleagues show that CD133 is a prognostic marker for BM patients and use patient-derived xenograft models of lung- and colon-BM to show that BM tumors respond to CD133-targeting CAR-T cell therapy. The authors saw significant inhibition of tumor progression and significant survival advantage in tumor-bearing mice after a single dose. This work establishes a clinically relevant prognostic marker for patients suffering from BM, and it advocates for a shift in the current standard of care to replace palliative treatments with ones that could dramatically improve the prognosis of patients.