Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics
Background Despite recent advances in immunotherapy, a substantial population of late-stage melanoma patients still fail to achieve sustained clinical benefit. Lack of translational preclinical models continues to be a major challenge in the field of immunotherapy; thus, more optimized translational...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2024-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/4/e008066.full |
| _version_ | 1797213551663775744 |
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| author | Lukas W Pfannenstiel Brian R Gastman Jennifer S Ko Marc S Ernstoff Pauline Funchain Yee Peng Phoon Jared E Lopes Heather C Losey Claudia Marcela Diaz-Montero Ye F Tian Raymond Winquist Jan Joseph Melenhorst |
| author_facet | Lukas W Pfannenstiel Brian R Gastman Jennifer S Ko Marc S Ernstoff Pauline Funchain Yee Peng Phoon Jared E Lopes Heather C Losey Claudia Marcela Diaz-Montero Ye F Tian Raymond Winquist Jan Joseph Melenhorst |
| author_sort | Lukas W Pfannenstiel |
| collection | DOAJ |
| description | Background Despite recent advances in immunotherapy, a substantial population of late-stage melanoma patients still fail to achieve sustained clinical benefit. Lack of translational preclinical models continues to be a major challenge in the field of immunotherapy; thus, more optimized translational models could strongly influence clinical trial development. To address this unmet need, we designed a preclinical model reflecting the heterogeneity in melanoma patients’ clinical responses that can be used to evaluate novel immunotherapies and synergistic combinatorial treatment strategies. Using our all-autologous humanized melanoma mouse model, we examined the efficacy of a novel engineered interleukin 2 (IL-2)-based cytokine variant immunotherapy.Methods To study immune responses and antitumor efficacy for human melanoma tumors, we developed an all-autologous humanized melanoma mouse model using clinically annotated, matched patient tumor cells and peripheral blood mononuclear cells (PBMCs). After inoculating immunodeficient NSG mice with patient tumors and an adoptive cell transfer of autologous PBMCs, mice were treated with anti-PD-1, a novel investigational engineered IL-2-based cytokine (nemvaleukin), or recombinant human IL-2 (rhIL-2). The pharmacodynamic effects and antitumor efficacy of these treatments were then evaluated. We used tumor cells and autologous PBMCs from patients with varying immunotherapy responses to both model the diversity of immunotherapy efficacy observed in the clinical setting and to recapitulate the heterogeneous nature of melanoma.Results Our model exhibited long-term survival of engrafted human PBMCs without developing graft-versus-host disease. Administration of an anti-PD-1 or nemvaleukin elicited antitumor responses in our model that were patient-specific and were found to parallel clinical responsiveness to checkpoint inhibitors. An evaluation of nemvaleukin-treated mice demonstrated increased tumor-infiltrating CD4+ and CD8+ T cells, preferential expansion of non-regulatory T cell subsets in the spleen, and significant delays in tumor growth compared with vehicle-treated controls or mice treated with rhIL-2.Conclusions Our model reproduces differential effects of immunotherapy in melanoma patients, capturing the inherent heterogeneity in clinical responses. Taken together, these data demonstrate our model’s translatability for novel immunotherapies in melanoma patients. The data are also supportive for the continued clinical investigation of nemvaleukin as a novel immunotherapeutic for the treatment of melanoma. |
| first_indexed | 2024-04-24T11:00:05Z |
| format | Article |
| id | doaj.art-be91f26ce0d14a72a9d770e7782a5e38 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-24T11:00:05Z |
| publishDate | 2024-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-be91f26ce0d14a72a9d770e7782a5e382024-04-12T01:55:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-04-0112410.1136/jitc-2023-008066Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeuticsLukas W Pfannenstiel0Brian R Gastman1Jennifer S Ko2Marc S Ernstoff3Pauline Funchain4Yee Peng Phoon5Jared E Lopes6Heather C Losey7Claudia Marcela Diaz-Montero8Ye F Tian9Raymond Winquist10Jan Joseph Melenhorst11Aff1 grid.239578.20000000106754725ImmunologyCleveland Clinic Cleveland OH USAMelanoma and High-Risk Skin Cancer Program, Cleveland Clinic Cancer Center, Cleveland, Ohio, USAAff1 grid.239578.20000000106754725ImmunologyLearner Research Institute at the Cleveland Clinic Cleveland OH USA14Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USACleveland Clinic Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA2Cleveland Clinic, Cleveland, OH, USAAlkermes Inc, Waltham, Massachusetts, USAResearch, Alkermes, Inc, Waltham, Massachusetts, USACenter for Immunotherapy and Precision Immuno-Oncology (CITI), Cleveland Clinic, Cleveland, Ohio, USADepartment of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USAAlkermes Inc, Waltham, Massachusetts, USACenter for Immunotherapy and Precision Immuno-Oncology (CITI), Cleveland Clinic, Cleveland, Ohio, USABackground Despite recent advances in immunotherapy, a substantial population of late-stage melanoma patients still fail to achieve sustained clinical benefit. Lack of translational preclinical models continues to be a major challenge in the field of immunotherapy; thus, more optimized translational models could strongly influence clinical trial development. To address this unmet need, we designed a preclinical model reflecting the heterogeneity in melanoma patients’ clinical responses that can be used to evaluate novel immunotherapies and synergistic combinatorial treatment strategies. Using our all-autologous humanized melanoma mouse model, we examined the efficacy of a novel engineered interleukin 2 (IL-2)-based cytokine variant immunotherapy.Methods To study immune responses and antitumor efficacy for human melanoma tumors, we developed an all-autologous humanized melanoma mouse model using clinically annotated, matched patient tumor cells and peripheral blood mononuclear cells (PBMCs). After inoculating immunodeficient NSG mice with patient tumors and an adoptive cell transfer of autologous PBMCs, mice were treated with anti-PD-1, a novel investigational engineered IL-2-based cytokine (nemvaleukin), or recombinant human IL-2 (rhIL-2). The pharmacodynamic effects and antitumor efficacy of these treatments were then evaluated. We used tumor cells and autologous PBMCs from patients with varying immunotherapy responses to both model the diversity of immunotherapy efficacy observed in the clinical setting and to recapitulate the heterogeneous nature of melanoma.Results Our model exhibited long-term survival of engrafted human PBMCs without developing graft-versus-host disease. Administration of an anti-PD-1 or nemvaleukin elicited antitumor responses in our model that were patient-specific and were found to parallel clinical responsiveness to checkpoint inhibitors. An evaluation of nemvaleukin-treated mice demonstrated increased tumor-infiltrating CD4+ and CD8+ T cells, preferential expansion of non-regulatory T cell subsets in the spleen, and significant delays in tumor growth compared with vehicle-treated controls or mice treated with rhIL-2.Conclusions Our model reproduces differential effects of immunotherapy in melanoma patients, capturing the inherent heterogeneity in clinical responses. Taken together, these data demonstrate our model’s translatability for novel immunotherapies in melanoma patients. The data are also supportive for the continued clinical investigation of nemvaleukin as a novel immunotherapeutic for the treatment of melanoma.https://jitc.bmj.com/content/12/4/e008066.full |
| spellingShingle | Lukas W Pfannenstiel Brian R Gastman Jennifer S Ko Marc S Ernstoff Pauline Funchain Yee Peng Phoon Jared E Lopes Heather C Losey Claudia Marcela Diaz-Montero Ye F Tian Raymond Winquist Jan Joseph Melenhorst Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics Journal for ImmunoTherapy of Cancer |
| title | Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics |
| title_full | Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics |
| title_fullStr | Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics |
| title_full_unstemmed | Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics |
| title_short | Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics |
| title_sort | autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics |
| url | https://jitc.bmj.com/content/12/4/e008066.full |
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