Dual‐Targeted Lipid Nanotherapeutic Boost for Chemo‐Immunotherapy of Cancer

Abstract

malignant cells. Immune checkpoint inhibitors (ICIs), such as anti-PD1 and anti-CTLA4 antibodies, are among the most successful immunotherapy modalities that have shown therapeutic benefits in various types of cancers, from melanoma to lung cancer. [1] However, only a minority of cancer patients are responsive to ICIs therapy, depending on their immunophenotype and cancer genotype. [2] Chemo-immunotherapy is a combination of "standard-of-care" chemotherapy with immunotherapy, mostly ICIs such as nivolumab and pembrolizumab that shows therapeutic benefit in the clinic and success in phase III trials. [3] Yet, many patients are still poorly responsive to this combination therapy and nanotherapeutics could be a novel strategy for the improvement of chemo-immunotherapy.The tumor immune microenvironment is enriched with various immune cells from myeloid cells to lymphocytes. Tumor myeloid cells including monocytes and macrophages are recruited by the inflamed cancer cell niche and paradoxically induce "immunosuppressive" status in solid tumors. [2b,4] In particular, tumor-associated macrophages (TAM) that are originated from tumor-infiltrated monocytes [5] directly remodel the tumor immune microenvironment by physically impeding infiltration of cytotoxic CD8 + T lymphocytes and Chemo-immunotherapy is a combination of "standard-of-care" chemotherapy with immunotherapy and it is considered the most advanced therapeutic modality for various types of cancers. However, many cancer patients still poorly respond to current regimen of chemo-immunotherapy and suggest nanotherapeutics as a boosting agent. Recently, heme oxygenase-1 (HO1) is shown to act as an immunotherapeutic molecule in tumor myeloid cells, in addition to general chemoresistance function in cancer cells suggesting that HO1-targeted therapeutics can become a novel, optimal strategy for boosting chemo-immunotherapy in the clinic. Currently the available HO1-inhibitors demonstrate serious adverse effects in clinical use. Herein, tumor myeloid cell-and cancer cell-dual targeted HO1-inhibiting lipid nanotherapeutic boost (T-iLNTB) is developed using RNAiloaded lipid nanoparticles. T-iLNTB-mediated HO1-inhibition sensitizes cancer cells to "standard-of-care" chemotherapeutics by increasing immunogenic cell death, and directly reprograms tumor myeloid cells with distinguished phenotype. Furthermore, tumor myeloid cell reprogramming by T-iLNTB induces CD8 + cytotoxic T cell recruitment, which drives "Cold-to-Hot" transition and correlates with improved responsiveness to immune checkpoint inhibitor in combination therapy. Finally, ex vivo study proves that HO1-inhibition directly affects tumor macrophage differentiation. This study demonstrates the potential of T-iLNTB as a novel therapeutic modality for boosting chemo-immunotherapy.

Lipid nanomaterials-based RNA therapy and cancer treatment

“…LNPs-based therapy targeting T cells have been developed for combination with surgery, chemotherapy, radiotherapy, and targeted pathway inhibition, as these are known to fight aggressive diseases by triggering the immune reactions of patients 108 . Various forms of cancer immunotherapy have emerged recently, and research into tumor-infecting viruses, cell therapy, cancer vaccines, immunogenic cell death, immune checkpoints, targeted antibodies, cytokines, and immune factor adjuvants has seen great progress.…”

Advancing mRNA technologies for therapies and vaccines: An African context

“…The authors were able to target a plethora of cell markers including CD44, CD34, CD3, CD4, CD25, CD29, Ly6C and Itgb7, and treat models of inflammatory bowel syndrome (IBS) and disseminated bone marrow mantle cell lymphoma by targeting siRNA to Ly6C and CD29, respectively. RNAi was also “dual targeted” using ASSET-LNPs targeting PD-L1 to sensitize cancer cells to chemotherapy, while immune-boosting myeloid cells by knockdown of heme oxigenase-1 ( 98 ). This approach was further adapted to deliver CRISPR mRNA and sgRNA, improving gene editing and survival compared to an IgG isotype LNP in an aggressive orthotopic glioblastoma model ( 99 ).…”

CIMT 2022: Report on the 19th Annual Meeting of the Association for Cancer Immunotherapy

“… 65 Using PD-L1-targeted LNPs for the delivery of heme-oxygenase-1 (HO1) silencing RNA to cancer and tumor-associated myeloid cells in B16F10 tumor-bearing mice improved the efficacy of chemotherapy and induced a proinflammatory response. 66 Presenting his “next generation selective targeting” approach, Peer explained how specificity can be achieved by targeting defined receptor conformations. 67 LNPs binding the high-affinity conformation of the lymphocyte-homing integrin α4β7 facilitated the selective delivery of IFNγ-silencing RNA to inflammatory gut-homing leukocytes, which reduced inflammation in experimental colitis.…”