Nanomedicine approaches for treatment of hematologic and oncologic malignancies

Table 1 Approved immune checkpoint inhibitors according to cancer type

Anti-CTLA-4 antibodies
Ipilimumab; Colorectal cancer; Melanoma; Renal cell carcinoma
Anti-PD-1 antibodies
Nivolumab; Bladder cancer; Colorectal cancer; Head and neck cancer; Hepatocellular carcinoma; Hodgkin lymphoma; Melanoma; Non-small-cell lung cancer; Renal cell carcinoma; Cemiplimab; Cutaneous squamous cell carcinoma; Pembrolizumab; Bladder cancer; Cervical cancer; Gastro-oesophageal junction cancers; Head and neck cancer; Hepatocellular carcinoma; Hodgkin lymphoma; Merkel cell carcinoma; Metastatic solid tumours classified as microsatellite instability high or deficient mismatch repair; Non-small-cell lung cancer; Primary mediastinal large B cell lymphoma; Stomach cancer
Anti-PD-L1 antibodies
Atezolizumab; Bladder cancer; Breast cancer; Non-small-cell lung cancer; Avelumab; Bladder cancer; Merkel cell carcinoma; Durvalumab; Bladder cancer; Non-small-cell lung cancer

Anti-CTLA-4: Anticytotoxic T lymphocyte-associated protein 4; PD-1: Programmed cell death protein - 1.

Table 2 Clinical trials on natural killer cells in hematological and solid tumors

Condition	Interventions	Phase	Ref.	Status
Solid tumor	ROBO1 CAR-NK cells	I/II	NCT03940820	Recruiting
Ewing sarcoma; Neuroblastoma; Rhabdomyosarcoma; Osteosarcoma; CNS tumors	Allogeneic HCT; Donor NK cell infusion	II	NCT02100891	Active, not recruiting
Brain and CNS tumors; leukemia; lymphoma; chronic myeloproliferative disorders; lymphoproliferative disorder multiple myeloma and plasma cell neoplasm; myelodysplastic syndrome; myelodysplastic/ myeloproliferative neoplasm; unspecified adult solid tumor, protocol specific	Donor NK cell infusion	I/II	NCT00823524	Completed
Malignant solid tumors	NK Immunotherapy	II	NCT02853903	Completed
Malignant solid tumors	NK Immunotherapy	I/II	NCT02857920	Completed
Multiple myeloma	CIML NK cells plus KP1237 and low dose IL-2	I/II	NCT04634435	Recruiting
Hematological malignancy;	NK cell infusion	I	NCT01853358	Completed
leukemia; lymphoma; myeloma; Hodgkin's disease	NK-92 cells	I	NCT00990717	Completed
Acute lymphoblastic leukemia; chronic lymphoblastic leukemia; B-cell lymphoma	Fludarabine + Cyclophosphamide + CAR-NK-CD19 Cells	I	NCT04796688	Recruiting
Leukemia; lymphoma	NK cell infusion	I	NCT01287104	Completed

NK: Natural killer.

Table 3 Summary of nanomedicines based on nucleic acids

Name	Category	Structure	Mode of action	Status
ASO	Inhibition of translation of cancer or angiogenesis associated proteins	Synthetic ssDNA or ssRNA oligos complementary to mRNA of interest	Rnase H mediated mRNA degradation	In clinical trials; LNP-based anti-Grb2 ASOs for leukemia[70] and solid tumors[71]; LNP-based anti-Bcl-2 ASOs for advanced lymphoid malignancies[72]
siRNA	Inhibition of translation of cancer or angiogenesis associated proteins	Synthetic dsRNA oligos complementary to mRNA of interest	Dicer induces cleavage of dsRNA and RNA-induced silencing complex mRNA degradation	In clinical trials; Polymeric anti-KRAS siRNAs for pancreatic ductal adenocarcinoma[78]; LNP based anti-PKN3 siRNAs in patients with advanced solid tumors[79]; LNP based anti-KSP and anti-VEGF-A siRNAs in patients with solid tumors[80,81]; LNP based anti-PLK1 siRNAs in patients with solid tumors[82]
saRNA	Forced exogenous gene expression	Synthetic dsRNA oligos complementary to mRNA of interest	Target gene promoters to induce transcriptional gene activation	In clinical trials; LNP based formulations for treatment of hepatocellular carcinoma[84] and advanced solid tumors[85]
miRNA mimics	Regulation of post- transcriptional mRNA expression	Chemically modified dsRNA molecules designed to mimic endogenous microRNAs	Translational repression and gene silencing	Currently only in basic research[87]
mRNA vaccines	Forced exogenous antigen expression	Synthetic mRNA	Induction of immune response against cancer cells	In clinical trials; LNP-based mRNA vaccines encoding known tumor-specific antigens are being investigated in early phase clinical trials in patients with HPV-driven squamous cell carcinoma[90], melanoma[90], ovarian[92], pancreatic, lung, and colorectal cancer[93]; Personalized vaccines based on patient specific neo-antigens are being assessed clinically for the treatment of melanoma[95] and breast cancer[96]

ASO: Antisense oligonucleotides; saRNA: Small activating RNA; siRNA: Small interfering RNAs; LNP: Lipid nanoparticle.