Acute myeloid leukaemia (AML) has a poor prognosis, especially in elderly and relapsed/refractory patients, with 5‑year survival below 30%.

Chemotherapy alone suffers from off‑target toxicity and drug resistance.

Immunotherapy offers precision and durable effects but shows limited efficacy as monotherapy.

Combining chemotherapy with immunotherapy is emerging as a promising paradigm.

This review summarises the rationale and advances of combining immune checkpoint inhibitors, CAR‑T, CAR‑NK, CAR‑macrophage therapies, antibody‑drug conjugates, bispecific antibodies, and cancer vaccines with chemotherapy for AML.

The study was recently published in the Oncology Advances.

We discuss preclinical and clinical progress, core challenges (off‑target toxicity, tumour heterogeneity, variable efficacy), and future directions toward precision medicine.

AML is a heterogeneous malignancy driven by clonal proliferation of abnormal myeloid progenitors.

Conventional therapies (chemotherapy, targeted agents, stem cell transplantation) have major limitations: severe toxicity, resistance, and donor shortage.

Immunotherapy can activate the host immune system against leukaemia stem cells, but single‑agent responses are modest.

Chemotherapy can reshape the tumour microenvironment (e.g., eliminate MDSCs/Tregs, downregulate PD‑L1, induce immunogenic cell death), creating synergy with immunotherapy.

This review covers five immunotherapeutic classes combined with chemotherapy: checkpoint inhibitors, CAR‑engineered cells, ADCs, bispecific antibodies, and cancer vaccines.

Combination with immune checkpoint inhibitors

• PD‑1/PD‑L1 and CTLA‑4 inhibitors: Pembrolizumab plus azacitidine (AZA) improved median OS to 10.8 months in R/R AML (vs <6 months historically). AZA plus nivolumab/ipilimumab showed better efficacy when used early. However, adding pembrolizumab to AZA+venetoclax did not improve outcomes. High‑dose cytarabine plus pembrolizumab increased CR rates.

• CD47 (macrophage checkpoint): Anti‑CD47 antibodies (e.g., magrolimab) combined with AZA showed early promise, but phase III trials (ENHANCE‑3) failed and were terminated due to increased mortality. Development in myeloid malignancies has been halted.

CAR‑Engineered immune cells

• CAR‑T: Challenges include target antigens shared with normal hematopoietic stem cells (e.g., CD33, CD123). CD44v6 CAR‑T targeting DNMT3A‑mutated AML shows synergy with decitabine. Anti‑CD123 CAR‑T plus hypomethylating agents (HMAs) enhance efficacy. Rapamycin pretreatment improves CAR‑T bone marrow infiltration.

• CAR‑NK: Advantages: no graft‑versus‑host disease, broader activity. CD33‑ and CD123‑targeted CAR‑NK cells are in trials. Preliminary data show minimal residual disease negativity in 6/10 R/R AML patients with acceptable safety, though excessive CAR‑NK proliferation caused concerns in one trial.

• CAR‑Macrophage (CAR‑M): Early preclinical stage. CAR‑M can phagocytose CD26‑positive CML cells or CD19‑expressing leukaemia cells. Promising but requires further validation.

Antibody‑Drug conjugates (ADCs)

• Gemtuzumab ozogamicin (GO, anti‑CD33): Approved for R/R AML. Addition to induction chemotherapy improves OS, especially in non‑adverse cytogenetics. Lintuzumab‑Ac225 (anti‑CD33) plus CLAG‑M achieved 67% CR/CRi in R/R AML.

• IMGN632 (anti‑CD123 ADC): Shows activity in R/R AML and BPDCN. Synergizes with venetoclax and AZA, particularly in FLT3‑ITD mutated AML, but less effective in TP53‑mutated disease. Phase Ib/II trials ongoing.

Bispecific antibodies (BsAbs)

• Flotetuzumab (CD123×CD3): In paediatric AML, adding cytarabine enhanced efficacy, even in moderate CD123 expression models. Combination overcomes limited monotherapy response.

• AMG330 (CD33×CD3): Induces PD‑L1 upregulation on AML cells via T‑cell activation, suggesting potential for combining with PD‑1/PD‑L1 blockade.

Tumour vaccines plus HMAs

Decitabine induces tumour‑associated antigens (e.g., WT1, NY‑ESO‑1).

Early trials combining decitabine with NY‑ESO‑1 vaccine (and nivolumab) generated CD4 T‑cell responses and increased immune activity.

This primes the immune system against AML cells.

Challenges and future directions

• Off‑target toxicity: CD33 and CD123 are also on normal hematopoietic progenitors → severe bone marrow suppression. New targets with higher specificity (CD70, ILT3, LAIR1) are under investigation.

• Tumour heterogeneity: Driver mutations (e.g., TP53) reduce immunogenicity and cause resistance. Multi‑target strategies and personalised regimens are needed.

• Immunosuppressive microenvironment: Combination with cytokines (IL‑7, IL‑12) or next‑generation CAR designs may improve efficacy.

• Future directions: Screen highly specific AML surface antigens; develop next‑generation CAR‑T/CAR‑NK/BsAbs/ADCs; establish individualised treatment based on mutation profile, antigen expression, and risk stratification.

Conclusions

Chemotherapy‑immunotherapy combinations break through the limitations of either modality alone.

PD‑(L)1 inhibitors plus HMAs, CD33/CD123 ADCs plus chemotherapy, CAR‑NK plus chemotherapy, and vaccines plus HMAs have shown promising clinical results, prolonging survival and improving remission rates in elderly and R/R AML.

However, off‑target toxicity, heterogeneity, and resistance remain.

Developing novel specific antigens, multi‑target interventions, and individualised precision medicine will be key to improving long‑term survival and quality of life for AML patients.

Source: Xia & He Publishing Inc.