Selected clinical trials that are testing new approaches to overcome immune escape in posttransplantation relapses
| Relapse modality . | Therapy . | Therapeutic intervention . | Trial number . | Phase . | Disease . | N . | Clinical outcomes . | Reference . |
|---|---|---|---|---|---|---|---|---|
| HLA loss | Cellular immunotherapies | CIML NK cell infusion | NCT03068819 | 1/2 | AML | 10 | CR: 25%; PR: 12.5%; PD: 50%; OS at 2 y follow-up: 42% | 37 |
| CART-38 | NCT04351022 | 1/2 | AML | 6 | CR: 66.7% (CR = 1; CRi = 3); OS and LFS at 6 mo follow-up: 50% | 38 | ||
| HLA loss and HLA class II downregulation | Bispecific antibodies | Flotetuzumab | NCT05506956 | 1b | AML | N/A | N/A | N/A |
| Flotetuzumab + DLI | NCT04582864 | 2 | AML, MDS | N/A | N/A | N/A | ||
| HLA class II downregulation | IFN-γ delivery | IFN-γ | NCT04628338 | Early phase 1 | AML, MDS | 4 | CR: 75% | 39 |
| p53-MDM2 inhibitors | Siremadlin (HDM201) ± DLI | NCT05447663 | 1/2 | AML | 38 | N/A | 40 | |
| Upregulation of T-cell-inhibitory ligands | ICI | Sabatolimab (MBG453/anti-TIM3) | NCT04623216 | 1/2 | AML | 21 | CR: 30%; no GVHD | 41 |
| Pembrolizumab | NCT02981914 | Early phase 1 | AML, MDS, HL, B-NHL | 12 | ORR: 22% (2/9), CR = 2, SD = 2, PD = 5; median follow-up: 4.4 y; PFS: 2.9 mo, OS: 23.3 mo | 42 | ||
| IPI or nivolumab | NCT01822509 | 1 | CLL, NHL, HL, MM, AML, ALL, MDS | 28 | ORR: 29%; OS and PFS at 1 y follow-up: 56% and 23%; GVHD: 39% | 43 | ||
| ICI + HMAs | Nivolumab + HMA | EudraCT 2017-002194-18 | 1/2 | AML | 16 | ORR: 25%; SD: 25%; PD: 12.5%; median PFS: 1.8 mo; median OS: 15.6 mo; aGVHD: 31.25%, cGVHD: 25% | 44 | |
| Nivolumab + Aza | NCT03825367 | 1/2 | AML | N/A | N/A | N/A | ||
| IPI + decitabine | NCT02890329 | 1 | AML, MDS | 25/48 | ORR = 20% | 45 | ||
| HMAs | Guadecitabine + DLI | NCT02684162 | 2 | AML, MDS | N/A | N/A | N/A | |
| Aza, lenalidomide + DLIs | NCT02472691 | 2 | MDS, sAML, CMML | 50 | ORR: 56%; 1-y OS: 65%; aGVHD: 46%, cGVHD: 52% | 46 | ||
| Azacytidine | NCT00887068 | 3 | AML, MDS | 187 | No benefit in treatment arm (RFS, OS rate); no difference in aGVHD-cGVHD | 47 | ||
| Metabolic rewiring of TME | Metabolic modulators | Bicanorm (NaBi) + DLIs | NCT04321161 | Early phase 1 | AML | 10 | Recovery of T-cell fitness, rewiring of acidic pH | 5 |
| Relapse modality . | Therapy . | Therapeutic intervention . | Trial number . | Phase . | Disease . | N . | Clinical outcomes . | Reference . |
|---|---|---|---|---|---|---|---|---|
| HLA loss | Cellular immunotherapies | CIML NK cell infusion | NCT03068819 | 1/2 | AML | 10 | CR: 25%; PR: 12.5%; PD: 50%; OS at 2 y follow-up: 42% | 37 |
| CART-38 | NCT04351022 | 1/2 | AML | 6 | CR: 66.7% (CR = 1; CRi = 3); OS and LFS at 6 mo follow-up: 50% | 38 | ||
| HLA loss and HLA class II downregulation | Bispecific antibodies | Flotetuzumab | NCT05506956 | 1b | AML | N/A | N/A | N/A |
| Flotetuzumab + DLI | NCT04582864 | 2 | AML, MDS | N/A | N/A | N/A | ||
| HLA class II downregulation | IFN-γ delivery | IFN-γ | NCT04628338 | Early phase 1 | AML, MDS | 4 | CR: 75% | 39 |
| p53-MDM2 inhibitors | Siremadlin (HDM201) ± DLI | NCT05447663 | 1/2 | AML | 38 | N/A | 40 | |
| Upregulation of T-cell-inhibitory ligands | ICI | Sabatolimab (MBG453/anti-TIM3) | NCT04623216 | 1/2 | AML | 21 | CR: 30%; no GVHD | 41 |
| Pembrolizumab | NCT02981914 | Early phase 1 | AML, MDS, HL, B-NHL | 12 | ORR: 22% (2/9), CR = 2, SD = 2, PD = 5; median follow-up: 4.4 y; PFS: 2.9 mo, OS: 23.3 mo | 42 | ||
| IPI or nivolumab | NCT01822509 | 1 | CLL, NHL, HL, MM, AML, ALL, MDS | 28 | ORR: 29%; OS and PFS at 1 y follow-up: 56% and 23%; GVHD: 39% | 43 | ||
| ICI + HMAs | Nivolumab + HMA | EudraCT 2017-002194-18 | 1/2 | AML | 16 | ORR: 25%; SD: 25%; PD: 12.5%; median PFS: 1.8 mo; median OS: 15.6 mo; aGVHD: 31.25%, cGVHD: 25% | 44 | |
| Nivolumab + Aza | NCT03825367 | 1/2 | AML | N/A | N/A | N/A | ||
| IPI + decitabine | NCT02890329 | 1 | AML, MDS | 25/48 | ORR = 20% | 45 | ||
| HMAs | Guadecitabine + DLI | NCT02684162 | 2 | AML, MDS | N/A | N/A | N/A | |
| Aza, lenalidomide + DLIs | NCT02472691 | 2 | MDS, sAML, CMML | 50 | ORR: 56%; 1-y OS: 65%; aGVHD: 46%, cGVHD: 52% | 46 | ||
| Azacytidine | NCT00887068 | 3 | AML, MDS | 187 | No benefit in treatment arm (RFS, OS rate); no difference in aGVHD-cGVHD | 47 | ||
| Metabolic rewiring of TME | Metabolic modulators | Bicanorm (NaBi) + DLIs | NCT04321161 | Early phase 1 | AML | 10 | Recovery of T-cell fitness, rewiring of acidic pH | 5 |
aGVHD, acute graft-versus-host disease; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CART, chimeric antigen receptor T cell; cGVHD, chronic GVHD; CLL, chronic lymphocytic leukemia; CMML, chronic myelomonocytic leukemia; CR, complete remission; CRi, complete remission with incomplete recovery; DLI, donor lymphocyte infusion; HL, Hodgkin lymphoma; LFS, leukemia-free survival; MDM2, mouse-double-minute-2; MM, multiple myeloma; N/A, not available; NHL, non-Hodgkin lymphoma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RFS, relapse-free survival; SD, stable disease.