Cancer cell membrane-coated nanoparticles for bimodal imaging-guided photothermal therapy and docetaxel-enhanced immunotherapy against cancer

Background Mono-therapeutic modality has limitations in combating metastatic lesions with complications. Although emerging immunotherapy exhibits preliminary success, solid tumors are usually immunosuppressive, leading to ineffective antitumor immune responses and immunotherapeutic resistance. The rational combination of several therapeutic modalities may potentially become a new therapeutic strategy to effectively combat cancer. Results Poly lactic-co-glycolic acid (PLGA, 50 mg) nanospheres were constructed with photothermal transduction agents (PTAs)-Prussian blue (PB, 2.98 mg) encapsulated in the core and chemotherapeutic docetaxel (DTX, 4.18 mg)/ immune adjuvant-imiquimod (R837, 1.57 mg) loaded in the shell. Tumor cell membranes were further coated outside PLGA nanospheres (designated “M@P-PDR”), which acted as “Nano-targeted cells” to actively accumulate in tumor sites, and were guided/monitored by photoacoustic (PA)/ magnetic resonance (MR) imaging. Upon laser irradiation, photothermal effects were triggered. Combined with DTX, PTT induced in situ tumor eradication. Assisted by the immune adjuvant R837, the maturation rate of DCs increased by 4.34-fold compared with that of the control. In addition, DTX polarized M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, relieving the immunosuppressive TME. The proportion of M2-TAMs decreased from 68.57% to 32.80%, and the proportion of M1-TAMs increased from 37.02% to 70.81%. Integrating the above processes, the infiltration of cytotoxic T lymphocytes (CTLs) increased from 17.33% (control) to 35.5%. Primary tumors and metastasis were significantly inhibited when treated with “Nano-targeted cells”-based cocktail therapy. Conclusion “Nano-targeted cells”-based therapeutic cocktail therapy is a promising approach to promote tumor regression and counter metastasis/recurrence. Graphical Abstract

860 The anti-tumor activity of HSP-90 therapeutic cancer vaccine (AST-021p) combine with TLR2/3 agonist in a MMTV-neu transgenic model

BackgroundAST-021p, which is derived from HLA class II binding epitopes of human HSP90 protein, is an investigational therapeutic cancer vaccine for the malignant neoplasms. AST-021p is designed to demonstrate the immunologic efficacy by activating antigen-specific CD4+ Th1 cell in humans. Due to their ability to link the innate with the adaptive immune response, Toll-like receptor (TLR) agonists are highly promising as adjuvants in vaccines against life-threatening and complex diseases such as cancer, AIDS and malaria. In this study, AST-021p was investigated to evaluate the immunogenicity and tumor growth inhibitory effect under the condition of combining with various immune adjuvants derived from TLR agonists, using in-vivo model.MethodsThree different agonists of TLR (TLR-4, TLR-2/3, TLR-7/8) were assigned to investigate the immunogenicity in each group (4 FVB mice/group, total 4 groups). AST-021p was intradermally injected 3 times with different TLR-agonists and the immunogenicity was assessed from mouse splenocyte by HSP90-specific IFN-γ ELISpot method. We also examined the efficacy of AST-021p and selected TLR-agonist in MMTVneu Tg mice (4 mice/group, conducted twice and A total 8 mice was assigned to each group). The combination of AST-021p and TLR-2/3 agonist (AST-021p plus TLR-2/3 agonist) was injected 3 times every 10 days to mice followed by inoculated mouse mammary cancer cell line. The tumor volume change and immunogenicity were evaluated.ResultsThe most effective TLR-agonist as a potent immune adjuvant was a TLR-2/3 agonist (L-pampoTM, supplied by CHA Vaccine Institute). In MMTV-Neu transgenic mice, AST-021p (100 μg) plus TLR-2/3 agonist significantly enhanced immunogenicity by increasing up to 130±10 HSP-90 epitope specific T cells per 1x105 splenocytes (P<0.001). AST-021p plus TLR-2/3 agonist also showed higher tumor growth inhibitory effect (170±108 mm3) on post-implantation 35th day by suppressing mouse mammary cancer cell line (5x105)-derived tumor growth, compared with a TLR-2/3 agonist alone (1031±450 mm3).ConclusionsCombination regimen of AST-021p and TLR-2/3 agonist (as immune adjuvant) demonstrated significant immunogenicity and tumor prevention effect in in-vivo study. These data supported the clinical study of AST-021p combined with TLR-2/3 agonist as active immune adjuvant in certain tumor types, and phase 1/2 clinical program would be expected to be initiated.AcknowledgementsNot applicableTrial RegistrationNot applicableReferencesCsermely P, Schnaider T, Soti C, Prohaszka Z, Nardai G. The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review. Pharmacol Ther 1998;79,129–168.Wang H, Lu M, Yao M, Zhu W. Effects of treatment with an Hsp90 inhibitor in tumors based on 15 phase II clinical trials. Mol Clin Oncol 2016;5,326–334.Ramalingam S, Goss G, Rosell R. Schmid-Bindert G, Zaric B, Andric Z, Bondarenko I, Komov D, Ceric T, Khuri F. A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1). Ann Oncol Off J Eur Soc Med Oncol 2015,26,1741–1748.Ethics ApprovalAll experimental procedures involving mice were performed with the guidance protocols approved by the Institutional Animal Care and Use Committee of Korea University (IACUC, Approval number: KOREA-2019-129)ConsentIt is not an abstract containing sensitive or identifiable information.

Artificial “Nano-Targeted Cells” for Bimodal Imaging-Guided Tumor Cocktail Therapy

Background: Single therapeutic modality always has its limitations in combating metastatic lesions with complicacy. Although the emerging immunotherapy exhibits preliminary success, solid tumors are usually immunosuppressive, leading to ineffective antitumor immune responses and immunotherapeutic resistance. Rational combination of several therapeutic modalities may potentially become a new therapeutic strategy to effectively combat cancer.Results: Poly lactic-co-glycolic acid (PLGA) nanospheres were constructed with photothermal transduction agents (PTAs)- Prussian blue (PB) encapsulated in the core and chemotherapeutic docetaxel (DTX)/ immune adjuvant- imiquimod (R837) loaded in the shell. Tumor cell membranes were further coated outside PLGA nanospheres (designated as “M@P-PDR”), which acted as “Nano-targeted cells” to actively accumulate in tumor sites, which was guided/monitored by photoacoustic (PA)/ magnetic resonance (MR) imaging. Upon laser irradiation, photothermal effects were triggered. Combined with DTX, PTT induced in situ tumor eradication. Assisted by immune adjuvant R837, the maturation of DCs were promoted. Besides, DTX polarized M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, relieving immunosuppressive TME. Integrating the above processes, the infiltration of cytotoxic T lymphocytes (CTLs) increased. The primary tumors and metastasis were significantly inhibited when treated with “Nano-targeted cells” based cocktail therapy.Conclusion: “Nano-targeted cells” based therapeutic cocktail therapy is a promising approach to promote tumor regression and counter metastasis/ recurrence.

Curcumin as an Adjuvant to Cancer Immunotherapy

The components of the immune system play a very sincere and crucial role in combating tumors. However, despite their firm efforts of elimination, tumor cells cleverly escape the surveillance process by adopting several immune evasion mechanisms. The conversion of immunogenicity of tumor microenvironment into tolerogenic is considered as a prime reason for tumor immune escape. Therapeutically, different immunotherapies have been adopted to block such immune escaping routes along with better clinical outcomes. Still, the therapies are haunted by several drawbacks. Over time, curcumin has been considered as a potential anti-cancer molecule. Its potentialities have been recorded against the standard hallmarks of cancer such as continuous proliferation, escaping apoptosis, continuous angiogenesis, insensitivity to growth inhibitors, tissue invasion, and metastasis. Hence, the diversity of curcumin functioning has already been established and exploration of its application with immunotherapies might open up a new avenue for scientists and clinicians. In this review, we briefly discuss the tumor’s way of immune escaping, followed by various modern immunotherapies that have been used to encounter the escaping paths and their minute flaws. Finally, the conclusion has been drawn with the application of curcumin as a potential immune-adjuvant, which fearlessly could be used with immunotherapies for best outcomes.

Final survival follow-up and translational associations using interval indirect immunization with oregovomab (O) and poly ICLC in patients (pts) with recurrent platinum-resistant ovarian cancer (PROC).

e17545 Background: Indirect immunization with tumor specific antibody is an approach to triggering therapeutic immunity to cancer through activated immune cells. O is a monoclonal IgG1 specific to CA125 (MUC16). O is currently in phase III evaluation of front-line chemoimmunotherapy (CIT), having shown benefit relative to chemotherapy alone in a randomized phase II study (Brewer, Gyn Onc 2020). H is a TLR3 agonist used as a stimulatory immune adjuvant. The dosing phase of the protocol established safety and compatibility of this combination. The primary safety and response outcomes were reported at IGCS-2019. Immune parameters and long-term outcome associations are the focus of this final update. Methods: Pts with heavily treated RECIST evaluable platinum resistant ovarian cancer (median of 5 prior Rx) received 4 IV infusions with 2 mg O followed by 2mg H IM 30 min & 48 hrs post O at wks 0, 3, 6, 9. At wk 12 imaging was performed and elective salvage Rx allowed. A fifth O+H was optional at wk 16. Study endpoints included immune associations after O+H, after second-line chemotherapy, and survival outcomes. Results: 17 pts were enrolled at 2 centers; 15 patients were dosed and 13 completed the specified minimum 3 infusions. The treatment was well tolerated with local reactions and mild flu like symptoms (13/15 pts) as the only reported adverse events. There was no treatment related serious adverse events. Median survival was 15.0 m [95% CI:10.8m-NE] and 4 patients remained alive at data lock (median 26.5 m). H stimulated an early humoral antibody response to O at wk 6 in 7 of 9 pts (78%). Interval administration of second-line Rx (bevacizumab, paclitaxel, carboplatin, &/or doxorubicin) and O were associated with further antibody spikes. Baseline neutrophil monocyte to lymphocyte ratio (NMLR), a measure of myeloid-derived immune suppression was inversely associated with survival. PROC patients with baseline NMLR ≤4x (n = 8) had median OS 19.6m [15.0 m -NE] vs median OS 10.8m [3.6m-NE] HR 2.44 [0.73-8.15], ( p= 0.13) for pts with NMLR > 4.0 (n = 7). Conclusions: H is a viable immune adjuvant for combination with O suitable for further study in immune resistant settings. Immune responsiveness was similar to that observed in a prior study of same day schedule of carboplatin-paclitaxel front-line immunotherapy (Braly, JIT 2009; Battaglia, Cll, 2020). Patterns of immune response to O in the setting of recurrent ovarian cancer are influenced by concomitant anti-neoplastic therapy. Clinical outcomes appear sensitive to myeloid burden (NMLR > 4) which may be more prevalent in patients with treatment resistant disease than in chemotherapy naïve patients, as previously observed in front-line CIT trials. A phase III study to further evaluate these associations in the front-line setting is currently underway NCT04498117. Clinical trial information: NCT03162562.

Identification and functional study of novel oligonucleotides: CpG Seq 13 and CpG Seq 19

Aim: This study explored new immunoadjuvants with stronger immune activity to enhance therapeutic effects against leukemia. Materials & methods: Whole blood and bone marrow of acute myeloid leukemia (AML) patients and healthy volunteers were collected. Isolated mononuclear cells were treated with two newly designed CpG oligodeoxynucleotides, CpG sequence 13 and 19, and known CpG oligodeoxynucleotides and analyzed via flow cytometry. Results: CpG Seq 13 and 19 possess strong immune activation and enhance the proliferation, degranulation and cytotoxicity of T cells. They also inhibit AML cell proliferation. When CpG Seq 13/19 are combined with anti-OX40 antibodies, the cytotoxicity of T cells on AML cells are further enhanced. Conclusion: CpG Seq 13 and 19 are strong immune adjuvant candidates for AML treatment.

Rapid Arc-SBRT: Non-invasive immune adjuvant for advanced stage Non-Small Cell Lung Carcinoma

: In conjunction with Radio-chemotherapy, pulmonary resection is recommended for early-stage Non-small-cell lung carcinoma but not for advanced-stage NSCLC patients with having high-grade metastatic lesions. In these cases, Rapid Arc-Stereotactic body radiotherapy (Ra-SBRT) technique offers a therapeutic advantage by delivering focal irradiation to metastatic lung lesions and reduces the bystander toxicity to normal tissues. We have previously demonstrated that Ra-SBRT ablates metastatic lesions and induces tumor immune rejection of metastatic tumors by promoting in situ programming of M2 TAM towards M1-TAM and infiltration of Siglec-8+ Eosinophils. Most interestingly, Ra SBRT has very low abscopal impact and spares normal tissues, which are the significant limitations with conventional radiotherapy. In view of this and Immune adjuvant potential of Ra SBRT, it promotes normalization of aberrant vasculature and inhibits the metastatic potential of NSCLC lesions. In view of this we here propose that Ra-SBRT indeed represents an immunogenic approach for the effective management of advanced-stage NSCLC.