Mechanisms of resistance to immunotherapy for B-cell acute lymphoblastic leukemia
| Mechanism of resistance . | Preclinical strategies . | Clinical studies . | |
|---|---|---|---|
| Leukemic intrinsic | CD19-negative disease | Splice variants, CD19 truncating mutations | CD22 CAR T cells |
| Identification of additional targets for therapy: TSLPR, CD123 | InO | ||
| Bispecific CD19 × CD22 targeting CAR T cells | |||
| CD22 downmodulation | Bryostatin to force expression of CD22 | ||
| Lineage switch | Lineage reprogramming from continued antigenic pressure | ||
| Identification of high-risk leukemias most susceptible to switch | |||
| Immunologic resistance | Exhaustion | Define optimal starting material and final product phenotype | Combination therapy with checkpoint blockade |
| Engineer overexpression of c-Jun | |||
| Directed integration of CAR into the TRAC locus | |||
| Design “armored CAR” to secrete checkpoint-blocking scFv | |||
| Rejection | Identification of epitope specificity of T-cell–mediated rejection | Humanized CAR constructs | |
| Fully human CAR constructs | |||
| Poor-quality lymphocytes | Identification of homeostatic cytokines to enhance expansion | Defined composition products with homeostatic cytokine support during cell expansion | |
| Inability to manufacture an autologous product | Universal CAR T cells | UCART19 | |
| CAR NK cells | Umbilical cord blood–derived NK cells with CD19 CAR, IL-15 secretion, and iC9 | ||
| Mechanism of resistance . | Preclinical strategies . | Clinical studies . | |
|---|---|---|---|
| Leukemic intrinsic | CD19-negative disease | Splice variants, CD19 truncating mutations | CD22 CAR T cells |
| Identification of additional targets for therapy: TSLPR, CD123 | InO | ||
| Bispecific CD19 × CD22 targeting CAR T cells | |||
| CD22 downmodulation | Bryostatin to force expression of CD22 | ||
| Lineage switch | Lineage reprogramming from continued antigenic pressure | ||
| Identification of high-risk leukemias most susceptible to switch | |||
| Immunologic resistance | Exhaustion | Define optimal starting material and final product phenotype | Combination therapy with checkpoint blockade |
| Engineer overexpression of c-Jun | |||
| Directed integration of CAR into the TRAC locus | |||
| Design “armored CAR” to secrete checkpoint-blocking scFv | |||
| Rejection | Identification of epitope specificity of T-cell–mediated rejection | Humanized CAR constructs | |
| Fully human CAR constructs | |||
| Poor-quality lymphocytes | Identification of homeostatic cytokines to enhance expansion | Defined composition products with homeostatic cytokine support during cell expansion | |
| Inability to manufacture an autologous product | Universal CAR T cells | UCART19 | |
| CAR NK cells | Umbilical cord blood–derived NK cells with CD19 CAR, IL-15 secretion, and iC9 | ||
CAR, chimeric antigen receptor; iC9, inducible caspase 9; InO, inotuzumab ozogamicin; NK, natural killer; scFv, single-chain variable fragment; TRAC, T-cell receptor α constant; TSLPR, thymic stromal lymphopoietin receptor.