Figure 2.
Postremission adoptive cellular therapy for high-risk acute leukemia. (1) Donor lymphocyte infusions aim to restore GvL and have been applied clinically to treat overt relapse posttransplant, prevent relapse in high-risk patients (prophylactic intent), and to restore GvL on impending relapse as defined by detection of MRD or LOC (preemptive intent). Several groups have refined this strategy with depletion and enrichment of specific T-cell subsets. Cytokine-induced killer cells (CIK) mimic an NK-like phenotype and are capable of HLA-unrestricted killing mediated through NKG2D and DAP10. (2) CTLs are primed ex vivo with leukemia-associated antigen (LAA) peptide mixes to redirect specificity. (3) Adoptive transfer of NK cells supports immune reconstitution early posttransplant. Ex vivo cytokine induction using interleukins-12, -15, -18 primes memory-like NK cells for enhanced killing. (4) CAR-modified NK cells are redirected for specific target engagement using a genetically engineered synthetic receptor. Logic-gated CAR-NK cells can discriminate between leukemic blasts and healthy progenitor cells by recognition of both activating and inhibitory stimuli. (5) CAR-T cells are genetically engineered to specifically recognize and kill targets in an HLA-unrestricted manner. Universal allogeneic CAR-T candidates are genetically edited for safe clinical use despite being derived from third-party donors. Dual-CAR-T constructs target multiple antigens simultaneously to circumvent immune escape arising from antigen-negative disease. TCR-engineered T cells recognize leukemia-associated antigens such as WT1 in an HLA-dependent manner. (6, 7) DLI combination therapy promises both synergistic antileukemic activity and immune modulation to augment GvL. Abbreviations: aCAR, activating chimeric antigen receptor; ADC, antibody-drug conjugate; Bcl-2, B-cell lymphoma-2; BiTE, bispecific T-cell engager; CAR, chimeric antigen receptor; CIK, cytokine-induced killer cells; CTL, cytotoxic T lymphocytes; DLI, donor lymphocyte infusion; HDACi, histone deacetylase inhibitor; HMA, hypomethylating agent; iCAR, inhibitory chimeric antigen receptor; LAA, leukemia-associated antigen; LOC, loss of complete donor chimerism; TCR, T-cell receptor; WT1, Wilms’ tumor protein. Image created in BioRender.

Postremission adoptive cellular therapy for high-risk acute leukemia. (1) Donor lymphocyte infusions aim to restore GvL and have been applied clinically to treat overt relapse posttransplant, prevent relapse in high-risk patients (prophylactic intent), and to restore GvL on impending relapse as defined by detection of MRD or LOC (preemptive intent). Several groups have refined this strategy with depletion and enrichment of specific T-cell subsets. Cytokine-induced killer cells (CIK) mimic an NK-like phenotype and are capable of HLA-unrestricted killing mediated through NKG2D and DAP10. (2) CTLs are primed ex vivo with leukemia-associated antigen (LAA) peptide mixes to redirect specificity. (3) Adoptive transfer of NK cells supports immune reconstitution early posttransplant. Ex vivo cytokine induction using interleukins-12, -15, -18 primes memory-like NK cells for enhanced killing. (4) CAR-modified NK cells are redirected for specific target engagement using a genetically engineered synthetic receptor. Logic-gated CAR-NK cells can discriminate between leukemic blasts and healthy progenitor cells by recognition of both activating and inhibitory stimuli. (5) CAR-T cells are genetically engineered to specifically recognize and kill targets in an HLA-unrestricted manner. Universal allogeneic CAR-T candidates are genetically edited for safe clinical use despite being derived from third-party donors. Dual-CAR-T constructs target multiple antigens simultaneously to circumvent immune escape arising from antigen-negative disease. TCR-engineered T cells recognize leukemia-associated antigens such as WT1 in an HLA-dependent manner. (6, 7) DLI combination therapy promises both synergistic antileukemic activity and immune modulation to augment GvL. Abbreviations: aCAR, activating chimeric antigen receptor; ADC, antibody-drug conjugate; Bcl-2, B-cell lymphoma-2; BiTE, bispecific T-cell engager; CAR, chimeric antigen receptor; CIK, cytokine-induced killer cells; CTL, cytotoxic T lymphocytes; DLI, donor lymphocyte infusion; HDACi, histone deacetylase inhibitor; HMA, hypomethylating agent; iCAR, inhibitory chimeric antigen receptor; LAA, leukemia-associated antigen; LOC, loss of complete donor chimerism; TCR, T-cell receptor; WT1, Wilms’ tumor protein. Image created in BioRender.

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