Blogs

Perioperative pembrolizumab in early-stage non-small cell lung cancer (NSCLC): safety, efficacy, and exploratory biomarker analysis

   Cameron Wood

Cameron Wood, Liliana Lyniv, James M Isaacs, Jacob M Kaufman, Eziafa I Oduah, Jeff Clarke, Jeffrey Crawford, Thomas Stinchcombe, Betty C Tong, Xiaofei Wang, Lin Gu, Dennis Wigle, Konstantin H Dragnev, Scott J Antonia, Kent Weinhold, Neal Ready
Journal for ImmunoTherapy of Cancer 2025;13:e010395 (4 February 2025)
RESEARCH

Summary:

Immune checkpoint inhibitors (ICI) are standard treatment for patients with non-small cell lung cancer (NSCLC).  Most patients with advanced disease, however, demonstrate primary or acquired ICI resistance. In this single-arm phase II study, patients with untreated stage IB to IIIA NSCLC received neoadjuvant pembrolizumab followed by surgical resection, standard adjuvant chemotherapy, and adjuvant pembrolizumab. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels were measured throughout treatment to assess its role as a possible biomarker for PD-1 checkpoint resistance. Perioperative pembrolizumab was shown to be safe and effective, with a 5-year progression-free survival of 72.0% and 5-year overall survival of 75.8%. Following surgical resection, major pathological response (MPR) and complete response were found in 28% and 4% of tumors, respectively. PCSK9 plasma levels increased over time, suggesting adaptive resistance to PD-1 checkpoint inhibition. Following surgical resection, PCSK9 plasma levels were lower in patients who experienced MPR compared with those who did not. This insight supports future research into PCSK9 inhibition, with readily available monoclonal antibodies in the clinic, to overcome PD-1 checkpoint resistance.  

Complete metabolic response as early predictor of long-term efficacy after adoptive T cell therapy using tumor-infiltrating lymphocytes

Troels Holz Borch

Troels Holz Borch, Rikke Andersen, Helle Westergren Hendel, Kasper Madsen, Eva Ellebaek, Inge Marie Svane
Journal for ImmunoTherapy of Cancer 2025;13:e010575 (6 February 2025)
SHORT REPORT

Summary:

Tumor infiltrating lymphocytes (TIL) have been successful in the treatment of patients with metastatic melanoma. Some patients, however, have progression following initial response. There is no established means to identify patients at risk for progression who may benefit from consolidation treatments. In this study, investigators compared radiologic and metabolic responses in 60 patients who had previously undergone TIL therapy for metastatic melanoma and had [18F]2-fluoro-2-deoxy-d-glucose positron emission tomography-CT (FDG-PET/CT) scans at baseline and follow-up. Patients with a partial response (PR) on radiologic testing were divided into two groups based on their metabolic response on FDG-PET/CT scan and were found to have significantly different clinical outcomes. In patients with PR and complete metabolic response (CMR), mean overall survival (mOS) and mean progressive-free survival (mPFS) were not reached, whereas in patients with PR but no CMR, mOS was 28.7 months (about 2 and a half years) and mPFS was 7.8 months. This demonstrates that CMR is a strong predictor of durability of response and supports the use of FDG/PET/CT scans to provide early prognostic information and tailor patient-specific management.

Pooled screening for CAR function identifies novel IL-13Rα2-targeted CARs for treatment of glioblastoma

Khloe S Gordon

Khloe S Gordon, Caleb R Perez, Andrea Garmilla, Maxine S Y Lam, Joey J Y Aw, Anisha Datta, Douglas A Lauffenburger, Andrea Pavesi, Michael E Birnbaum
Journal for ImmunoTherapy of Cancer 2025;13:e00957 (11 February 2025)
RESEARCH

Summary:

Chimeric antigen receptor (CAR)-T cell therapy is of particular interest in the treatment of glioblastoma (GBM) given the ability of T cells to cross the blood brain barrier and limited effective therapeutic options for this disease. While CAR-T cell therapy has been successful in patients with hematologic malignancies, precise tuning of both the signaling architecture and structural elements of the CAR may be required to translate this success to solid tumors. In this study, investigators used a pooled screening platform, CARPOOL, to expedite the discovery of CARs targeting the cancer testis antigen IL-13Rα1, which is commonly expressed in GBM. Using this method, they examined CD4+ CARs that persist, proliferate, differentiate, and kill tumor cells. Each enriched CAR successfully produced the phenotype for which it was selected. One of these CARs triggered potent antitumor cytotoxicity and long-term persistence. These results support the use of platforms such as CARPOOL to identify functional CARs in future research. 

Enhanced thrombopoiesis supplies PD-L1 to circulating immune cells via the generation of PD-L1-expressing platelets in patients with lung cancer

Sung-Woo Lee, Saei Jeong, Young Ju Kim, Jeong Eun Noh, Kyung Na Rho, Hee-Ok Kim, Hyun-Ju Cho, Deok Hwan Yang, Eu Chang Hwang, Woo Kyun Bae, Sook Jung Yun, Ju Sik Yun, Cheol-Kyu Park, In-Jae Oh, Jae-Ho Cho
Journal for ImmunoTherapy of Cancer 2025;13:e010193 (26 February 2025)
RESEARCH

Summary:

PD-L1 is expressed on multiple circulating immune cells, including T, B, and NK cells. With thrombopoiesis, murine models demonstrate enhanced PD-L1 expression on megakaryocytes and platelets associated with wound healing. Similarly in patients with non-small cell lung cancer, as well as those with stage IV bladder cancer and bile duct cancer, enhanced expression of PD-L1 on platelets was observed, particularly with CD41⁺/integrin alpha 2b⁺ platelets. Direct correlation of these findings with upregulation on T, B, and NK cells was observed as well as response to therapy. Thus, upregulation on platelets is a natural phenomenon under the conditions of enhanced thrombopoiesis. Expression of platelet PD-L1 seems to regulate immune responses in patients. Thrombopoiesis-induced expression of platelet PD-L1 is an example of another mechanism that promotes evasion of immunity by the tumor cells. These findings allow the critical examination of CD41⁺ platelets with PD-L1 expression as a biomarker predicting response.