Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design
Background Successful development of chimeric antigen receptor (CAR) T cell immunotherapy for children and adults with relapsed/refractory acute myeloid leukemia (AML) is highly desired given their poor clinical prognosis and frequent inability to achieve cure with conventional chemotherapy. Initial...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2021-09-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/9/e003149.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832557465109004288 |
|---|---|
| author | Haiying Qin Nirali N Shah Terry J Fry Lila Yang John A Chukinas Samiksha Tarun Marie Pouzolles Christopher D Chien Lisa M Niswander Anthony R Welch Sarah K Tasian Naomi A Taylor |
| author_facet | Haiying Qin Nirali N Shah Terry J Fry Lila Yang John A Chukinas Samiksha Tarun Marie Pouzolles Christopher D Chien Lisa M Niswander Anthony R Welch Sarah K Tasian Naomi A Taylor |
| author_sort | Haiying Qin |
| collection | DOAJ |
| description | Background Successful development of chimeric antigen receptor (CAR) T cell immunotherapy for children and adults with relapsed/refractory acute myeloid leukemia (AML) is highly desired given their poor clinical prognosis and frequent inability to achieve cure with conventional chemotherapy. Initial experiences with CD19 CAR T cell immunotherapy for patients with B-cell malignancies highlighted the critical impact of intracellular costimulatory domain selection (CD28 vs 4-1BB (CD137)) on CAR T cell expansion and in vivo persistence that may impact clinical outcomes. However, the impact of costimulatory domains on the efficacy of myeloid antigen-directed CAR T cell immunotherapy remains unknown.Methods In this preclinical study, we developed six CAR constructs targeting CD33, a highly expressed and validated AML target, comprised of one of three single-chain variable fragments with CD3ζ and either CD28 or 4-1BB costimulatory domains. We systematically compared the preclinical in vitro and in vivo efficacy of T cells lentivirally transduced with CD33 CAR constructs (CD33CARTs) against human AML.Results We observed potent in vitro cytokine production and cytotoxicity of CD33CARTs incubated with human CD33+ AML cell lines, as well as robust in vivo antileukemia activity in cell line and childhood AML patient-derived xenograft (PDX) models. Gemtuzumab-based CD33CARTs were unexpectedly toxic in vivo in animal models despite observed in vitro anti-leukemia activity. CD28-based CD33CARTs consistently induced more robust inhibition of leukemia proliferation in AML cell line and PDX models than did 4-1BB-based CD33CARTs. A ‘best-in-class’ lintuzumab-CD28/CD3ζ CAR construct was thus selected for clinical translation.Conclusions CD33 is a critical antigen for potential immunotherapeutic targeting in patients with AML. Based on this rigorous preclinical evaluation, our validated clinical grade lintuzumab-CD28/CD3ζ CD33CART immunotherapy is now under evaluation in a first-in-child/first-in-human phase 1 clinical trial for children and adolescents/young adults with relapsed/refractory AML.Trial registration number clinicaltrials.gov; NCT03971799. |
| format | Article |
| id | doaj-art-7341e3e04ef748e4ab7d4e2752aa2b98 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-09-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-7341e3e04ef748e4ab7d4e2752aa2b982025-02-03T04:40:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-09-019910.1136/jitc-2021-003149Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct designHaiying Qin0Nirali N Shah1Terry J Fry2Lila Yang3John A Chukinas4Samiksha Tarun5Marie Pouzolles6Christopher D Chien7Lisa M Niswander8Anthony R Welch9Sarah K Tasian10Naomi A Taylor11National Institutes of Health, Bethesda, Maryland, USAPediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAUniversity of Colorado Denver Children`s Hospital Colorado Research Institute, Aurora, Colorado, USANational Institutes of Health, Bethesda, Maryland, USADivision of Oncology and Center for Childhood Cancer Research, The Children`s Hospital of Philadelphia, Philadelphia, Pennsylvania, USANational Institutes of Health, Bethesda, Maryland, USA1NIH, Bethesda, MD, USANational Institutes of Health, Bethesda, Maryland, USADivision of Oncology and Center for Childhood Cancer Research, The Children`s Hospital of Philadelphia, Philadelphia, Pennsylvania, USANational Institutes of Health, Bethesda, Maryland, USADivision of Oncology and Center for Childhood Cancer Research, The Children`s Hospital of Philadelphia, Philadelphia, Pennsylvania, USANational Institutes of Health, Bethesda, Maryland, USABackground Successful development of chimeric antigen receptor (CAR) T cell immunotherapy for children and adults with relapsed/refractory acute myeloid leukemia (AML) is highly desired given their poor clinical prognosis and frequent inability to achieve cure with conventional chemotherapy. Initial experiences with CD19 CAR T cell immunotherapy for patients with B-cell malignancies highlighted the critical impact of intracellular costimulatory domain selection (CD28 vs 4-1BB (CD137)) on CAR T cell expansion and in vivo persistence that may impact clinical outcomes. However, the impact of costimulatory domains on the efficacy of myeloid antigen-directed CAR T cell immunotherapy remains unknown.Methods In this preclinical study, we developed six CAR constructs targeting CD33, a highly expressed and validated AML target, comprised of one of three single-chain variable fragments with CD3ζ and either CD28 or 4-1BB costimulatory domains. We systematically compared the preclinical in vitro and in vivo efficacy of T cells lentivirally transduced with CD33 CAR constructs (CD33CARTs) against human AML.Results We observed potent in vitro cytokine production and cytotoxicity of CD33CARTs incubated with human CD33+ AML cell lines, as well as robust in vivo antileukemia activity in cell line and childhood AML patient-derived xenograft (PDX) models. Gemtuzumab-based CD33CARTs were unexpectedly toxic in vivo in animal models despite observed in vitro anti-leukemia activity. CD28-based CD33CARTs consistently induced more robust inhibition of leukemia proliferation in AML cell line and PDX models than did 4-1BB-based CD33CARTs. A ‘best-in-class’ lintuzumab-CD28/CD3ζ CAR construct was thus selected for clinical translation.Conclusions CD33 is a critical antigen for potential immunotherapeutic targeting in patients with AML. Based on this rigorous preclinical evaluation, our validated clinical grade lintuzumab-CD28/CD3ζ CD33CART immunotherapy is now under evaluation in a first-in-child/first-in-human phase 1 clinical trial for children and adolescents/young adults with relapsed/refractory AML.Trial registration number clinicaltrials.gov; NCT03971799.https://jitc.bmj.com/content/9/9/e003149.full |
| spellingShingle | Haiying Qin Nirali N Shah Terry J Fry Lila Yang John A Chukinas Samiksha Tarun Marie Pouzolles Christopher D Chien Lisa M Niswander Anthony R Welch Sarah K Tasian Naomi A Taylor Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design Journal for ImmunoTherapy of Cancer |
| title | Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design |
| title_full | Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design |
| title_fullStr | Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design |
| title_full_unstemmed | Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design |
| title_short | Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design |
| title_sort | systematic preclinical evaluation of cd33 directed chimeric antigen receptor t cell immunotherapy for acute myeloid leukemia defines optimized construct design |
| url | https://jitc.bmj.com/content/9/9/e003149.full |
| work_keys_str_mv | AT haiyingqin systematicpreclinicalevaluationofcd33directedchimericantigenreceptortcellimmunotherapyforacutemyeloidleukemiadefinesoptimizedconstructdesign AT niralinshah systematicpreclinicalevaluationofcd33directedchimericantigenreceptortcellimmunotherapyforacutemyeloidleukemiadefinesoptimizedconstructdesign AT terryjfry systematicpreclinicalevaluationofcd33directedchimericantigenreceptortcellimmunotherapyforacutemyeloidleukemiadefinesoptimizedconstructdesign AT lilayang systematicpreclinicalevaluationofcd33directedchimericantigenreceptortcellimmunotherapyforacutemyeloidleukemiadefinesoptimizedconstructdesign AT johnachukinas systematicpreclinicalevaluationofcd33directedchimericantigenreceptortcellimmunotherapyforacutemyeloidleukemiadefinesoptimizedconstructdesign AT samikshatarun systematicpreclinicalevaluationofcd33directedchimericantigenreceptortcellimmunotherapyforacutemyeloidleukemiadefinesoptimizedconstructdesign AT mariepouzolles systematicpreclinicalevaluationofcd33directedchimericantigenreceptortcellimmunotherapyforacutemyeloidleukemiadefinesoptimizedconstructdesign AT christopherdchien systematicpreclinicalevaluationofcd33directedchimericantigenreceptortcellimmunotherapyforacutemyeloidleukemiadefinesoptimizedconstructdesign AT lisamniswander systematicpreclinicalevaluationofcd33directedchimericantigenreceptortcellimmunotherapyforacutemyeloidleukemiadefinesoptimizedconstructdesign AT anthonyrwelch systematicpreclinicalevaluationofcd33directedchimericantigenreceptortcellimmunotherapyforacutemyeloidleukemiadefinesoptimizedconstructdesign AT sarahktasian systematicpreclinicalevaluationofcd33directedchimericantigenreceptortcellimmunotherapyforacutemyeloidleukemiadefinesoptimizedconstructdesign AT naomiataylor systematicpreclinicalevaluationofcd33directedchimericantigenreceptortcellimmunotherapyforacutemyeloidleukemiadefinesoptimizedconstructdesign |