Adoptive immunotherapies have emerged as a promising strategy in the treatment of hematological malignancies. To date, seven chimeric antigen receptor (CAR)-T cell products have obtained market authorization in Europe for B-cell malignancies, where they have revolutionized treatment for eligible patients. In addition, natural killer (NK) cells and γδ T cells are of particular interest for cell-based therapies due to their strong intrinsic cytotoxicity and favorable safety profile. Addressing challenges facing the clinical translation of NK cell therapies was one of the issues discussed in the NK & ILC Symposium that took place in Freiburg, Germany from March 11 to 13, 2026, as the annual meeting of the NK & ILC study group of the German Society for Immunology (DGfI). Topics ranging from basic immunological research to technological innovations and clinical trial results were discussed during the 3-day conference, spanning over 40 presentations and 100 posters. A highlight of the conference was a workshop featuring short presentations and a panel discussion that focused specifically on the current challenges and future prospects of the clinical implementation of NK cell therapies; the findings of this workshop are summarized in this opinion paper. Graphical abstract
L. Knapp, Katharina Sophie Fischer, Janika Sosat et al.· Human Gene Therapy· 0 citations
Small cell lung cancer (SCLC) is an aggressive form of lung cancer, with most patients showing poor response rates to immunotherapies, resulting in limited treatment options. Profiling of the SCLC TIME shows immunologic heterogeneity, with the majority of SCLC being neuroendocrine (NE) subtype and exhibiting low MHC-I expression, and a minority being non-neuroendocrine (non-NE) subtype, with higher MHC-I expression. Recent incorporation of T cell engagers targeting DLL3 and CD3 have shown promising results, however, MHC-I downregulation can potentially limit endogenous T cell activity and therapeutic responses. Chimeric antigen receptor (CAR) based therapies enable the genetic engineering of T or NK cells to target tumor-specific antigens independently of MHC-I, representing a promising therapeutic strategy for SCLC. However, CAR-NK cells’ proliferation and lifespan is limited compared to CAR-T cells. CAR-T might benefit from a combination with CAR-NK providing a rapid antitumor response to promote infiltration and expansion. In this study we aimed to use 3D micro-physiological systems to test whether a combination of CAR-T and CAR-NK could overcome CAR therapy limitations in solid tumors.
DLL3 surface protein expression was characterized in SCLC cell lines by flow cytometry. Then, DLL3-targeting CAR-T and CAR-NK cells were generated through viral transduction and validated in both 2D and 3D tumor models. The combination of the CAR-T and CAR-NK was tested using a co-culture spheroids model in a 3D microfluidic device. Finally, infiltration of the CARs across a blood vessel barrier into the TME was investigated by creating a microphysiological system of SCLC TME.
We found that DLL3 expression was heterogenous across SCLC cell lines, with NE SCLC exhibiting higher DLL3 expression than non-NE SCLC. Both DLL3 CAR-T and CAR-NK cells demonstrated potent antitumor activity in 2D and 3D culture, with CAR-NK cells showing more rapid cytotoxic activity compared to CAR-T cells, killing via antigen recognition but also recognizing the absence of MHC-I expression. We then sought to combine both therapies to investigate cooperative activity between the two effector-cell platforms. At a 6-day timepoint, without exogenous IL-2 stimulation, we found that the DLL3 CAR-T and CAR-NK cell combination showed the greatest anti-tumor activity in the DLL3+ NE cell lines, compared to either therapy alone when tested in the 3D microfluidic model, suggesting synergistic and bystander effector function. These results correlated with higher IL-2 and IFN-g production detected in conditioned media only in the CAR-T and CAR-NK cell combination treatment.
These results suggest that DLL3-targeting CAR therapies represent a promising approach for treating SCLC, particularly given their ability to function independently of MHC-I. In addition, a combination of CAR-T and CAR-NKs could be an efficacious approach to overcoming current limitations of CAR therapies in solid tumors, including immune cell exclusion, persistence, and exhaustion.
Alan E. Bers, Ian Gillanders, Eden Bobilev, Carla Stornante, Mubin Tarannum, Navin R. Mahadevan, Rizwan Romee, Marco Campisi, David A. Barbie. DLL3 CAR-T and CAR-NK cell combination therapy promotes synergistic antitumor activity in small cell lung cancer [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr PR009.
Alan E. Bers, I. Gillanders, Eden Bobilev et al.· Clinical Cancer Research· 0 citations
Small cell lung cancer (SCLC) is an aggressive form of lung cancer, with most patients showing poor response rates to immunotherapies, resulting in limited treatment options. Profiling of the SCLC TIME shows immunologic heterogeneity, with the majority of SCLC being neuroendocrine (NE) subtype and exhibiting low MHC-I expression, and a minority being non-neuroendocrine (non-NE) subtype, with higher MHC-I expression. Recent incorporation of T cell engagers targeting DLL3 and CD3 have shown promising results, however, MHC-I downregulation can potentially limit endogenous T cell activity and therapeutic responses. Chimeric antigen receptor (CAR) based therapies enable the genetic engineering of T or NK cells to target tumor-specific antigens independently of MHC-I, representing a promising therapeutic strategy for SCLC. However, CAR-NK cells’ proliferation and lifespan is limited compared to CAR-T cells. CAR-T might benefit from a combination with CAR-NK providing a rapid antitumor response to promote infiltration and expansion. In this study we aimed to use 3D micro-physiological systems to test whether a combination of CAR-T and CAR-NK could overcome CAR therapy limitations in solid tumors.
DLL3 surface protein expression was characterized in SCLC cell lines by flow cytometry. Then, DLL3-targeting CAR-T and CAR-NK cells were generated through viral transduction and validated in both 2D and 3D tumor models. The combination of the CAR-T and CAR-NK was tested using a co-culture spheroids model in a 3D microfluidic device. Finally, infiltration of the CARs across a blood vessel barrier into the TME was investigated by creating a microphysiological system of SCLC TME.
We found that DLL3 expression was heterogenous across SCLC cell lines, with NE SCLC exhibiting higher DLL3 expression than non-NE SCLC. Both DLL3 CAR-T and CAR-NK cells demonstrated potent antitumor activity in 2D and 3D culture, with CAR-NK cells showing more rapid cytotoxic activity compared to CAR-T cells, killing via antigen recognition but also recognizing the absence of MHC-I expression. We then sought to combine both therapies to investigate cooperative activity between the two effector-cell platforms. At a 6-day timepoint, without exogenous IL-2 stimulation, we found that the DLL3 CAR-T and CAR-NK cell combination showed the greatest anti-tumor activity in the DLL3+ NE cell lines, compared to either therapy alone when tested in the 3D microfluidic model, suggesting synergistic and bystander effector function. These results correlated with higher IL-2 and IFN-g production detected in conditioned media only in the CAR-T and CAR-NK cell combination treatment.
These results suggest that DLL3-targeting CAR therapies represent a promising approach for treating SCLC, particularly given their ability to function independently of MHC-I. In addition, a combination of CAR-T and CAR-NKs could be an efficacious approach to overcoming current limitations of CAR therapies in solid tumors, including immune cell exclusion, persistence, and exhaustion.
Alan E. Bers, Ian Gillanders, Eden Bobilev, Carla Stornante, Mubin Tarannum, Navin R. Mahadevan, Rizwan Romee, Marco Campisi, David A. Barbie. DLL3 CAR-T and CAR-NK cell combination therapy promotes synergistic antitumor activity in small cell lung cancer [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B056.
Alan E. Bers, I. Gillanders, Eden Bobilev et al.· Clinical Cancer Research· 0 citations
