SUMMARY
The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4–1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts.
In many cancers, the tumor microenvironment
(TME) is largely immune
suppressive, blocking the antitumor immunity and resulting in immunotherapy
resistance. Interleukin 10 (IL-10) is a major player controlling the
immunosuppressive TME in different murine tumor models. Increased
IL-10 production suppresses intratumoral dendritic cell production
of interleukin 12, thereby limiting antitumor cytotoxic T-cell responses
and activation of NK cells during therapy. We engineered, formulated,
and delivered genes encoding an IL-10 protein trap to change immunosuppressive
TME, which could enhance antitumor immunity. Additionally, to achieve
stronger and long-term therapeutic efficacy in a pancreatic cancer
model, we targeted C-X-C motif chemokine ligand 12 (CXCL12), a key
factor for inhibiting T-cell tumor infiltration, and simultaneously
delivered an IL-10 trap. Following three injections of the lipid-protamine-DNA
(LPD) nanoparticles loaded with trap genes (IL-10 trap and CXCL12
trap), we found tumor growth reduction and significantly prolonged
survival of the host compared to control groups. Furthermore, the
combination trap gene treatment significantly reduced immunosuppressive
cells, such as M2 macrophages, MDSCs, and PD-L1+ cells,
and activated immunosuppressive tolerogenic dendritic cells, NK cells,
and macrophages intratumorally. We have also shown that, when effectively
delivered to the tumor, the IL-10 trap gene alone can inhibit triple-negative
breast cancer growth. This strategy may allow clinicians and researchers
to change the immunosuppressive microenvironment in the tumor with
either a single therapeutic agent or in combination with other immunotherapies
to prime the immune system, preventing cancer invasion and prolonging
patient survival.
The development and progression of colorectal cancer (CRC) is closely related to gut microbiome. Here we investigated the impact of lipopolysaccharide (LPS), one of the most prevalent products in the gut microbiome, on CRC immunotherapy. We found that LPS was abundant in orthotopic CRC tissue and was associated with low responses to anti-PD-L1 mAb therapy, and clearance of Gram-negative bacteria from the gut using polymyxin B (PmB), or blockade of Toll-like receptor 4 using TAK-242, would both relieve the immunosuppressive microenvironment and boost T-cell infiltration into the CRC tumor. Further, we designed an engineered LPS-targeting fusion protein and loaded its coding sequence into a lipid-protamine-DNA (LPD) nanoparticle system for selectively expression of LPS trap protein and blocking LPS inside the tumor, and this nano-trapping system significantly relieved the immunosuppressive microenvironment and boosted anti-PD-L1 mAb therapy against CRC tumor. This LPS trap system even attenuated CRC liver metastasis when applied, suggesting the importance of blocking LPS in the gut-liver axis. The strategy applied here may provide a useful new way for treating CRC as well as other epithelial cancers that interact with mucosa microbiome.
Development of an effective treatment against advanced tumors remains a major challenge for cancer immunotherapy. Approximately 50% of human melanoma is driven by B-Raf proto-oncogene mutation (BRAF mutant). Tumors with such mutation are desmoplastic, highly immunosuppressive, and often resistant to immune checkpoint therapies. We have shown that immunotherapy mediated by low-dose doxorubicin-induced immunogenic cell death was only partially effective for this type of tumor and not effective in long-term inhibition of tumor progression. Wnt family member 5A (Wnt5a), a signaling protein highly produced by BRAF mutant melanoma cells, has been implicated in inducing dendritic cell tolerance and tumor fibrosis, thus hindering effective antigen presentation and T-cell infiltration. We hypothesized that Wnt5a is a key molecule controlling the immunosuppressive tumor microenvironment in metastatic melanoma. Accordingly, we have designed and generated a trimeric trap protein, containing the extracellular domain of Fizzled 7 receptor that binds Wnt5a with a K ∼ 278 nM. Plasmid DNA encoding for the Wnt5a trap was delivered to the tumor by using cationic lipid-protamine-DNA nanoparticles. Expression of Wnt5a trap in the tumor, although transient, was greater than that of any other major organs including liver, resulting in a significant reduction of the Wnt5a level in the tumor microenvironment without systematic toxicity. Significantly, combination of Wnt5a trapping and low-dose doxorubicin showed great tumor growth inhibition and host survival prolongation. Our findings indicated that efficient local Wnt5a trapping significantly remodeled the immunosuppressive tumor microenvironment to facilitate immunogenic cell-death-mediated immunotherapy.
Liver malignancies are among the tumor types that are resistant to immune checkpoint inhibition therapy. Tumor‐associated macrophages (TAMs) are highly enriched and play a major role in inducing immunosuppression in liver malignancies. Herein, CCL2 and CCL5 are screened as two major chemokines responsible for attracting TAM infiltration and inducing their polarization toward cancer‐promoting M2‐phenotype. To reverse this immunosuppressive process, an innovative single‐domain antibody that bispecifically binds and neutralizes CCL2 and CCL5 (BisCCL2/5i) with high potency and specificity is directly evolved. mRNA encoding BisCCL2/5i is encapsulated in a clinically approved lipid nanoparticle platform, resulting in a liver‐homing biomaterial that allows transient yet efficient expression of BisCCL2/5i in the diseased organ in a multiple dosage manner. This BisCCL2/5i mRNA nanoplatform significantly induces the polarization of TAMs toward the antitumoral M1 phenotype and reduces immunosuppression in the tumor microenvironment. The combination of BisCCL2/5i with PD‐1 ligand inhibitor (PD‐Li) achieves long‐term survival in mouse models of primary liver cancer and liver metastasis of colorectal and pancreatic cancers. The work provides an effective bispecific targeting strategy that could broaden the PD‐Li therapy to multiple types of malignancies in the human liver.
In breast cancer model, we identified C–C Motif Chemokine Ligand 2 (CCL2) as the key mediator which is secreted by tumor associated adipocytes, and developed targeted lipid-protamine-DNA (LPD) nanoparticles to locally “trap” CCL2 to ameliorate the immunosuppressive tumor microenvironment.
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