bims-tuinly 2025-11-02 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–11–02
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Tumour-infiltrating lymphocyte therapy comes of age in the era of genetic engineering.
Prognostic value of tumor-infiltrating lymphocytes (TILs) in Luminal breast cancer: A novel computational method for assessing TILs abundance and spatial distribution patterns.
Multi-Modal Biomarker Profiling of Tumor Microenvironment and Genomic Alterations to Enhance Immunotherapy Stratification in Melanoma.
Roles of Tumor-Infiltrating Lymphocytes and Antitumor Immune Responses as Predictive and Prognostic Markers in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy.
Immune Checkpoint Therapy for Thymic Carcinoma.
Multimodal reprogramming of the tumor microenvironment by MMR and dual checkpoint blockade in hepatocellular carcinoma models.
[Current progress and latest therapeutic options in immuno-oncology].
Artificial intelligence-powered spatial analysis of tumor microenvironment in patients with non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitor.
CD8-Guided Immunochemotherapy Improves Pathological Complete Response Rates in High Tumor Burden Triple-Negative Breast Cancer.
Targeting LAG3 to alter the tumor immune reactivity of CD8+T cells is a potential therapy for skin cutaneous melanoma.
Transcriptional regulator SATB1 limits CD8+ T cell population expansion and effector differentiation in chronic infection and cancer.
CD70-Targeting CAR-NK Cells Overcome BCMA Downregulation and Improve Survival in High-Risk Multiple Myeloma Models.

Lancet Oncol. 2025 Nov;pii: S1470-2045(25)00434-6. [Epub ahead of print]26(11): e577-e585

Tumour-infiltrating lymphocyte therapy comes of age in the era of genetic engineering.

Michael D Crowther, Joel E Sohlin, Inge Marie Svane, Özcan Met.

Advances in cancer immunotherapy from immune checkpoint modulation to adoptive cell transfer of tumour-infiltrating lymphocytes (TILs) have greatly improved outcomes for patients with advanced cancers, particularly metastatic melanoma. The approval of TIL therapy in 2024 following two independent landmark clinical trials has established this approach as a viable treatment option, with response rates of up to 50% in treatment-resistant melanoma. Genetic engineering offers new opportunities to further improve TIL efficacy and durability, including viral vector-mediated overexpression of cytokines or chimeric receptors, and non-viral genome editing techniques such as CRISPR-Cas9 to delete inhibitory genes such as PD-1 and CISH. In this Review we outline the current state of genetically engineered TILs, highlighting both preclinical advances and ongoing clinical trials. As these engineered products are evaluated in clinical settings, they are expected to expand the personalised immunotherapy toolkit and improve durable outcomes across a broader range of solid tumours.

DOI: https://doi.org/10.1016/S1470-2045(25)00434-6
Breast. 2025 Oct 25. pii: S0960-9776(25)00651-4. [Epub ahead of print]84 104634

Prognostic value of tumor-infiltrating lymphocytes (TILs) in Luminal breast cancer: A novel computational method for assessing TILs abundance and spatial distribution patterns.

Xi Cai, Yuying Chen, Qianqian Li, Tongxin Wei, Yachun Yang, Rui Ye, Xue Chao, Mei Li, Jiehua He, Rongzhen Luo, Shuoyu Xu, Peng Sun.

  The prognostic significance of tumor-infiltrating lymphocytes (TILs) in Luminal-type breast cancer remains controversial, primarily due to typically low TIL infiltration levels, methodological inconsistencies in assessment, and insufficient consideration of spatial distribution patterns. To overcome these limitations, we developed an advanced artificial intelligence (AI)-driven computational TIL assessment (CTA) system, compliant with international visual assessment guidelines, which enables precise quantification of both TIL abundance (automatic TILs, aTILs) and spatial distribution patterns (aggregated: aTILs-agg; distributed: aTILs-dis) in Luminal-type breast cancer. Our comprehensive analysis suggests that elevated TIL levels were significantly associated with improved overall survival (OS) and progression-free survival (PFS) outcomes. Notably, Luminal B subtype demonstrated significantly higher TIL infiltration compared to Luminal A. In the Luminal A cohort, the aggregated spatial pattern (aTILs-agg) emerged as a favorable prognostic indicator for both OS and PFS, while in Luminal B cases, overall TIL abundance (aTILs) and distributed patterns (aTILs-dis) were associated with enhanced survival outcomes. Multivariate Cox regression analysis confirmed the independent prognostic value of aTILs, aTILs-agg, and aTILs-dis for PFS in Luminal A patients, though no significant associations were observed in the Luminal B subgroup. This study demonstrates the clinical utility of AI-powered TIL assessment as a promising prognostic indicator for predicting clinical outcomes in Luminal breast cancer patients, offering new insights into tumor-immune interactions within this molecular subtype.

Keywords:  Artificial intelligence; Luminal-type breast cancer; Prognosis; Spatial distribution; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.breast.2025.104634
Curr Issues Mol Biol. 2025 Oct 03. pii: 821. [Epub ahead of print]47(10):

Multi-Modal Biomarker Profiling of Tumor Microenvironment and Genomic Alterations to Enhance Immunotherapy Stratification in Melanoma.

Meshack Bida, Thabiso Victor Miya, Tebogo Marutha, Rodney Hull, Mohammed Alaouna, Zodwa Dlamini.

  Tumor mutational burden (TMB) and tumor-infiltrating lymphocytes (TILs) are key biomarkers for predicting immunotherapy responses in cutaneous melanoma. The discordance between brisk TIL morphology and absent cytokine signals complicates immune profiling. We examined the interactions between TMB, TIL patterns, cytokine expression, and genomic alterations to uncover immune escape mechanisms and refine prognostic tools. A structure-based BRAF druggability analysis was performed to anchor the genomic findings in a therapeutic context. Primary cutaneous melanoma cases (N = 205) were classified as brisk (n = 65), non-brisk (n = 60), or absent TILs (n = 80) according to the American association for cancer research (AACR) guidelines. Inter-observer concordance was measured using intraclass correlation. Tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels were graded using immunohistochemistry. Eleven brisk TIL cases lacking TNF-α expression were analyzed using the (Illumina TruSight Oncology 500, Illumina-San Diego, CA, USA). Dabrafenib docking to the BRAF ATP site was performed with Glide SP/XP and rescored with Prime MM-GBSA. Brisk TILs lacking cytokine signals suggested post-translational silencing of TNF-α/IFN-γ. Among the 11 profiled cases, eight exhibited high TMB and copy number alterations, with enrichment of nine metastasis/immune regulation genes. Inter-observer concordance was high (absent TILs, 95%; brisk TILs, 90.7%). BRAF docking yielded a canonical type-I pose and strong ATP pocket engagement (ΔG_bind -84.93 kcal·mol-1). Single biomarkers are insufficient for diagnosis. A multiparametric framework combining histology, cytokine immunohistochemistry (IHC), and genomic profiling enhances stratification and reveals immune escape pathways, with BRAF modeling providing a mechanistic anchor for the targeted therapy.

Keywords:  copy number variations; cutaneous melanoma; cytokine signaling; genomic profiling; immune checkpoint inhibitors; immune escape; tumor mutational burden; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/cimb47100821
Int J Mol Sci. 2025 Oct 13. pii: 9959. [Epub ahead of print]26(20):

Roles of Tumor-Infiltrating Lymphocytes and Antitumor Immune Responses as Predictive and Prognostic Markers in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy.

Ryungsa Kim, Takanori Kin, Koji Arihiro.

  Tumor-infiltrating lymphocytes (TILs) are thought to play important roles in tumor shrinkage and survival prolongation in patients with breast cancer receiving neoadjuvant chemotherapy (NAC). TILs are mononuclear immune cells such as lymphocytes and plasma cells, including CD4+ and CD8+ T cells, natural killer cells, B cells, macrophages, regulatory T cells (Tregs), and myeloid/dendritic cells. The pre-NAC presence of more T cells and fewer Tregs in biopsy samples of primary breast tumors is known to contribute to tumor shrinkage and prolonged survival. This review was conducted to elucidate these roles in patients with breast cancer treated with NAC. Publications selected for inclusion in this review were identified by a PubMed search for articles published in English, performed using the terms "breast cancer", "neoadjuvant chemotherapy", "tumor-infiltrating lymphocyte", "pathological complete response", and "immune response". The search was completed in July 2024. The functional roles of TILs in the achievement of these outcomes may vary by tumor subtype; increases and decreases in TIL levels before and after NAC have been shown to have conflicting effects. Biomarkers have been reported to predict local responses in the tumor microenvironment (e.g., immune-related gene signatures) and systemic immune responses (e.g., neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios). Immune gene signatures and immune cell infiltration do not appear to be universally associated with tumor response or outcome in patients with breast cancer treated with NAC. The functional roles of TILs in breast tumor response and breast cancer survival may vary by tumor subtype, and conflicting results for the same subtypes may be due to differences in NAC regimens, immune responses, tumor heterogeneity, sample size, and the technical methods used to evaluate TILs in tumor samples.

Keywords:  breast cancer; immune response; neoadjuvant chemotherapy; pathological complete response; tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.3390/ijms26209959
Cancers (Basel). 2025 Oct 20. pii: 3377. [Epub ahead of print]17(20):

Immune Checkpoint Therapy for Thymic Carcinoma.

Jinhui Li, Fuling Mao, Hongyu Liu, Jun Chen.

  Thymic carcinoma (TC) is a rare, aggressive cancer that originates from thymus's epithelial cells. It distinguishes itself from other thymic epithelial tumors with its unique pathological structure, clinical behavior, and immune characteristics. Immune checkpoint inhibitors (ICIs) targeting the Programmed cell death protein 1/Programmed cell death protein ligand 1 (PD-1/PD-L1) pathway have shown promise in advanced TC, potentially benefiting from frequent PD-L1 overexpression and abundant CD8+ tumor-infiltrating lymphocytes (TILs), despite typically low tumor mutational burden (TMB). While ICI monotherapy can achieve disease control in some patients, its overall efficacy is limited and it is associated with a distinct profile of immune-related adverse events (irAEs) which occur less often than in thymomas. The predictive value of biomarkers-particularly PD-L1 expression-remains uncertain, underscoring the importance of consistent assessment criteria. In this review, we summarize evidence on ICI monotherapy as well as combination approaches that incorporate anti-angiogenic agents, chemotherapy, or dual checkpoint blockade. Emerging therapeutic targets-such as CD70, TIM-3, and B7-H4-are also considered in the context of their potential clinical relevance. Finally, we discuss future directions aimed at improving efficacy, extending response durability, and reducing treatment-related toxicity through biomarker-based patient selection and tailored therapeutic strategies.

Keywords:  immune checkpoints inhibitors; immune-related adverse events; programmed cell death protein 1; programmed cell death protein ligand 1; thymic carcinoma

DOI:  https://doi.org/10.3390/cancers17203377
Front Immunol. 2025 ;16 1679665

Multimodal reprogramming of the tumor microenvironment by MMR and dual checkpoint blockade in hepatocellular carcinoma models.

Mulu Z Tesfay, Aleksandra Cios, Khandoker Usran Ferdous, Randal S Shelton, Bahaa Mustafa, Camila C Simoes, Murat Gokden, Isabelle R Miousse, Kimberly J Krager, Marjan Boerma, Alicja Urbaniak, Anuradha Kunthur, Sri Obulareddy, Joshua M Eichhorn, Steven R Post, Jean Christopher Chamcheu, Omeed Moaven, Chiswili Y Chabu, Dan G Duda, Matteo Conti, Bruno Nardo, Rang Govindarajan, Martin E Fernandez-Zapico, Lewis R Roberts, Mitesh J Borad, Martin J Cannon, Alexei G Basnakian, Bolni M Nagalo.

  Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, thus, there is an urgent need to develop more effective therapeutic options for this dismal condition. Tumor-infiltrating lymphocytes (TILs) are associated with improved response to immune checkpoint blockade in HCC, but their low abundance in most cases limits their therapeutic efficacy. Here, we demonstrate, in mice, that low-dose intratumoral immunovirotherapy with the trivalent measles, mumps, and rubella vaccine (MMR) induces superior tumor-growth delay and extended host survival compared to individually administered vaccines for measles, mumps, or rubella viruses. Further, our results show that MMR therapy synergizes with PD-1 and CTLA-4 blockade to reprogram the tumor microenvironment, resulting in increased CD8+ TIL infiltration and reduced PD-1 expression on TILs, among other effects. These changes in the immunological landscape translated into greater survival and more durable tumor-specific and memory immune responses for hosts. Comprehensive toxicology analysis revealed no evidence of MMR-induced liver or kidney toxicity after intrahepatic administration. This work reinforces an unrecognized role of MMR plus ICB in reprogramming the immune landscape in HCC through multimodal immune activation, providing a strong rationale for further development of MMR-based therapies for HCC.

Keywords:  MMR vaccine; hepatocellular carcinoma; immune checkpoint blockade; innate and adaptive immunity modulation; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1679665
Dtsch Med Wochenschr. 2025 Nov;150(22): 1335-1340

[Current progress and latest therapeutic options in immuno-oncology].

Sebastian Kobold, Rasmus Müller.

Recently approved immunotherapeutic agents in Europe mostly consist of monoclonal antibody-based products. For solid cancers, these comprise the antibody-drug-conjugate Mirvetuximab Soravtansine for platinum-resistant ovarian cancer, the monoclonal antibody Zolbetuximab for Claudin-18.2 positive gastric adenocarcinoma and the checkpoint inhibitor Tislelizumab for esophageal squamous cell carcinoma. For the treatment of relapsed or refractory hematologic B cell malignancies, the use of bispecific T cell engaging antibodies like the BCMA-CD3 targeting Teclistamab and CD20-CD3 targeting Glofitamab were approved by the EMA recently.Combinatorial approaches of conventional chemotherapy and checkpoint inhibitors for the treatment of cholangiocarcinoma, urothelial carcinoma and endometrial carcinoma received recent approval.A CD38 antibody-based bridging therapy for the treatment of newly diagnosed multiple myeloma and the Glofitamab-based approach in combination with Gemcitabine and Oxaliplatin for relapsed DLBCL are the latest additions for hematologic malignancies after promising clinical trials.The first T cell products for the treatment of solid cancers using either tumor-infiltrating lymphocytes or TCR-engineered peripheral blood T cells were approved by the FDA in 2024, for the treatment of advanced melanoma (Lifileucel) and synovial sarcoma (Afamitresgene autoleucel). To further expand the success of T cell products to solid tumors, promising preclinical studies suggest solutions to main obstacles, such as modular CAR T cells, targeting of two antigens simultaneously or generation of cytokine-secreting 4th generation CAR T cells.

DOI: https://doi.org/10.1055/a-2502-1305
J Immunother Cancer. 2025 Oct 31. pii: e012374. [Epub ahead of print]13(10):

Artificial intelligence-powered spatial analysis of tumor microenvironment in patients with non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitor.

Yeong Hak Bang, Geun-Ho Park, Jin Woo Oh, Soohyun Hwang, Jun-Gi Jeong, Boram Lee, Cheol Yong Joe, Hyemin Kim, Jinyong Kim, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Yoon-La Choi, Chang Ho Ahn, Siraj M Ali, Chan-Young Ock, Se-Hoon Lee.

   PURPOSE: This study evaluated the dynamic changes in the tumor microenvironment (TME) in patients with non-small cell lung cancer (NSCLC) and acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) using an artificial intelligence (AI)-powered spatial TME analyzer. We then assessed the predictive efficacy of immune-checkpoint inhibitors (ICIs)-based treatment.
EXPERIMENTAL DESIGN: An AI-powered whole-slide image analyzer was used to segment cancer areas (CAs) and cancer stroma and to identify tumor-infiltrating lymphocytes (TILs), tertiary lymphoid structures, fibroblasts, and endothelial cells (ECs) in the tumor tissue. We analyzed 143 NSCLC samples after resistance to EGFR-TKIs from two cohorts: (1) 89 patients treated with ICI monotherapy and (2) 54 patients from the ATTLAS phase III trial comparing atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP) versus pemetrexed plus carboplatin.
RESULTS: Post-TKI samples showed reduced TILs in the CA (p=0.045) and increased ECs in the CA (p=0.005) compared with pre-TKI samples. These changes differed according to EGFR mutation subtype. Higher TILs in CA were associated with a better overall response rate (ORR) and progression-free survival (PFS). Similarly, higher EC levels in CA correlated with improved ORR and PFS. In the ATTLAS cohort, these factors were associated with clinical benefits from ABCP, with a significant association with TILs and a marginal association with ECs.
CONCLUSION: Our findings suggest that EGFR-TKIs affect the immune landscape of patients with EGFR-mutated NSCLC. Higher TILs or ECs in the CA were significantly associated with a favorable response to subsequent ICI-based treatment.
TRIAL REGISTRATION NUMBER: NCT03991403.

Keywords:  biomarker; lung cancer; tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2025-012374
Mol Ther. 2025 Oct 30. pii: S1525-0016(25)00931-1. [Epub ahead of print]

CD8-Guided Immunochemotherapy Improves Pathological Complete Response Rates in High Tumor Burden Triple-Negative Breast Cancer.

Li Chen, Shu-Hao Jiang, Guang-Yu Liu, Ke-Da Yu, Jiong Wu, Gen-Hong Di, Wen-Juan Zhang, Lin-Xiaoxi Ma, Qian-Nan Liang, Yu Shen, Zhong-Hua Wang, Zhi-Ming Shao, Jun-Jie Li.

Blockade of the programmed cell death 1 ligand 1 (PD-L1) enhances the efficacy of standard chemotherapy in the neoadjuvant treatment of triple-negative early breast cancer (TNBC) but is associated with adverse events. This phase 2 trial evaluated camrelizumab (anti-PD-1) combined with chemotherapy in locally advanced immunomodulatory TNBC (CD8+ T-cell infiltration ≥ 10%). From October 2022 to September 2023, 90 stage II-III TNBC patients were randomized to receive neoadjuvant chemotherapy ± camrelizumab (200 mg biweekly). The camrelizumab-chemotherapy group (n = 45) achieved a pathological complete response (pCR) rate of 62.2% (95% CI:46.5-76.2%) versus 42.2% (27.7-57.8%) in the chemotherapy-alone group (n = 45), with a 20.0% absolute increase (P = 0.059). Grade ≥ 3 adverse events occurred in 88.9% (40/45) and 82.2% (37/45) of patients, respectively. Multi-omics analyses demonstrated significantly elevated CD8+T-cell infiltration in camrelizumab-treated pCR patients, alongside strong correlations between PD-L1 expression, stromal tumor-infiltrating lymphocytes (sTILs), and CD8+ density. These results indicate that CD8-guided immunochemotherapy with camrelizumab improves pCR rates in high tumor burden TNBC with manageable toxicity, supporting CD8+ T-cell levels as a predictive biomarker for immunotherapy response.

DOI: https://doi.org/10.1016/j.ymthe.2025.10.056
Sci Rep. 2025 Oct 29. 15(1): 37910

Targeting LAG3 to alter the tumor immune reactivity of CD8+T cells is a potential therapy for skin cutaneous melanoma.

Jin Gong, Yan Zhao, Shaozhi Gong, Chunyu Deng, Yajie Zhou.

  CD8+ T cells exert a significant effect in immune infiltration, drug resistance and cell survival in cancers, but the roles and mechanisms in skin cutaneous melanoma (SKCM) remain unclear. In the present study, prognostic biomarkers associated with CD8+ T cell subsets were screened, and the significance of CD8+ T cells in SKCM immunotherapy was explored by integrated single-cell RNA sequencing (scRNA-seq) and Bulk RNA sequencing (Bulk RNA-seq) analyses. Based on scRNA-seq analysis, CD8 + T cells were divided into two subgroups: CD8 + LAG3 + T cells and CD8 + LAG3-T cells. Cell-cell communication analysis revealed that both subsets closely interact with melanoma cells. Differential gene expression analysis showed that LAG3 was up-regulated in SKCM, and immune infiltration analysis showed that the survival prognosis was significantly better in the Score-High group than in the Score-Low group. Assay results demonstrated that both the LAG3 inhibitor ZYF0033 and the monoclonal antibody Miptenalimab significantly suppressed tumor proliferation and metastasis, while enhancing immune cell infiltration in murine models. This study revealed the functional heterogeneity of CD8 + T cells in SKCM and demonstrated that LAG3 inhibition suppresses tumor proliferation and metastasis. Moreover, reduced LAG3 expression significantly enhanced CD8 + T cell immune infiltration, highlighting the regulatory role of LAG3 in CD8 + T cell function within the tumor microenvironment. These findings provided further evidence that SKCM may be effectively treated by targeting LAG3.

Keywords:  Bulk RNA-seq; CD8+ t cells; Immunotherapy; LAG3; scRNA-seq

DOI:  https://doi.org/10.1038/s41598-025-22377-5
Nat Immunol. 2025 Oct 27.

Transcriptional regulator SATB1 limits CD8+ T cell population expansion and effector differentiation in chronic infection and cancer.

Leonie Heyden, Lisa Rausch, Michael H Shannon, Lachlan Dryburgh, Marcela L Moreira, Aleksej Frolov, Christina M Scheffler, Marit J van Elsas, Junming Tong, Olivia Hidajat, Sharanya K M Wijesinghe, Sining Li, Helena Horvatic, Nhat Truong Huynh-Anh, Catarina Gago da Graça, Carlson Tsui, Maren Köhne, Daniel Sommer, F Thomas Wunderlich, Bianca von Scheidt, Simone L Park, Laura K Mackay, Daniel T Utzschneider, Jan Schröder, Stephen J Turner, Phillip K Darcy, Marc D Beyer, Zeinab Abdullah, Axel Kallies.

CD8+ T cells are major mediators of antiviral and antitumor immunity. During persistent antigen stimulation as in chronic infection and cancer, however, they differentiate into exhausted T cells that display impaired functionality. Precursors of exhausted T (TPEX) cells exhibit stem-like properties, including high proliferative, self-renewal and developmental potential, and are responsible for long-term CD8+ T cell responses against persistent antigens. Here we identify the chromatin organizer and transcriptional regulator SATB1 as a major regulator of exhausted CD8+ T cell differentiation. SATB1 was specifically expressed in TPEX cells where it limited population expansion and effector differentiation while preserving functionality of CD8+ T cells. SATB1 downregulation was required for TPEX cell-to-effector cell differentiation in chronic infection and contributed to coordinated effector and memory differentiation in acute viral infection. DNA binding of SATB1 regulated gene expression both dependent and independent of chromatin accessibility. Finally, SATB1 limited antitumor CD8+ and chimeric antigen receptor T cell immunity. Overall, our results identify SATB1 as a central regulator of precursor fate and effector differentiation of CD8+ T cells both in infection and in cancer.

DOI: https://doi.org/10.1038/s41590-025-02316-2
Blood Cancer Discov. 2025 Oct 27.

CD70-Targeting CAR-NK Cells Overcome BCMA Downregulation and Improve Survival in High-Risk Multiple Myeloma Models.

Paul Lin, Sunil Acharya, Francia Reyes-Silva, Rafet Basar, Nadima Uprety, Luz Yurany Moreno Rueda, Pei Lin, April L Gilbert, Pinaki P Banerjee, Dexing Fang, Chenyu Zhang, Ana Karen Nunez Cortes, Luciana Melo Garcia, May Daher, Luis Muniz-Feliciano, Gary M Deyter, Vernikka Woods, Seema Rawal, Ping Li, Corry M Jones, Rejeena Shrestha, Muzaffar H Qazilbash, Krina K Patel, Hans C Lee, Richard E Champlin, David Marin, Elizabeth J Shpall, Robert Z Orlowski, Katayoun Rezvani.

CD70 is highly expressed in many cancers, including multiple myeloma (MM). We show in two cohorts of patients with MM that CD70 is elevated in several high-risk disease categories and correlates with poor survival. These findings were validated using single-cell RNA sequencing, flow cytometry and immunohistochemistry. Moreover, we demonstrate the feasibility of targeting CD70 in myeloma using natural killer (NK) cells engineered with a chimeric antigen receptor (CAR) incorporating the CD70 cognate receptor CD27 and IL-15. CAR27/IL-15 NK cells exerted potent in vitro and in vivo cytotoxicity against CD70+ MM cells, comparable to CAR27/IL-15 T cells, and remained effective in BCMA-knockout models. Collectively, these results establish CD70 as a promising therapeutic target for high-risk MM, particularly for patients who relapse after BCMA-directed therapy, providing preclinical support for the ongoing phase I/II clinical trial of CD70-targeting CAR-NK cells (NCT05092451).

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0130