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. 2020 Mar 4;6(10):eaaz4204.
doi: 10.1126/sciadv.aaz4204. eCollection 2020 Mar.

Localized cocktail chemoimmunotherapy after in situ gelation to trigger robust systemic antitumor immune responses

Yu Chao  1 , Chao Liang  1 , Huiquan Tao  1 , Yaran Du  1 , Di Wu  1 , Ziliang Dong  1 , Qiutong Jin  1 , Guobin Chen  1 , Jun Xu  1 , Zhisheng Xiao  1 , Qian Chen  1 , Chao Wang  1 , Jian Chen  1 , Zhuang Liu  1
Affiliations

Localized cocktail chemoimmunotherapy after in situ gelation to trigger robust systemic antitumor immune responses

Yu Chao et al. Sci Adv. .

Abstract

Currently, there is a huge demand to develop chemoimmunotherapy with reduced systemic toxicity and potent efficacy to combat late-stage cancers with spreading metastases. Here, we report several "cocktail" therapeutic formulations by mixing immunogenic cell death (ICD)-inducing chemotherapeutics and immune adjuvants together with alginate (ALG) for localized chemoimmunotherapy. Immune checkpoint blockade (ICB) antibody may be either included into this cocktail for local injection or used via conventional intravenous injection. After injection of such cocktail into a solid tumor, in-situ gelation of ALG would lead to local retention and sustained release of therapeutics to reduce systemic toxicity. The chemotherapy-induced ICD with the help of immune adjuvant would trigger tumor-specific immune responses, which are further amplified by ICB to elicit potent systemic antitumor immune responses in destructing local tumors, eliminating metastases and inhibiting cancer recurrence. Our strategy of combining clinically used agents for tumor-localized cocktail chemoimmunotherapy possesses great potential for clinical translation.

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Figures

Fig. 1
Fig. 1. Preparation and characterization of the drug composition.
(A) Scheme illustrating local chemoimmunotherapy using various drug composites. (B) Photographs showing lyophilized powders of drug composites containing OXA/R837/anti-PDL1/ALG or DOX/R837/anti-PDL1/ALG, which, after being dissolved into aqueous solutions, could rapidly form hydrogels after adding calcium ions. (C) SEM image of the gel scaffold loaded with OXA and R837. Scale bar, 100 μm. (D to G) Rheology properties of ALG gels formed at different ALG concentrations in Ca2+-containing phosphate-buffered saline (PBS). (H to K) Cumulative release profiles of OXA (H), DOX (I), R837 (J), and aPDL1 (K) from hydrogels incubated in PBS. Data are means ± SEM. IgG, immunoglobulin G. Photo credit (A and B): Yu Chao, Soochow University.
Fig. 2
Fig. 2. Local administration of chemoimmunotherapeutic drug composite to elicit immunogenic tumor phenotypes.
(A) CT26 tumors harvested from mice with intravenous injection of OXA/R837/ALG were analyzed by flow cytometry 7 days after the treatment. (B to E) Representative flow cytometric plots of immune cell infiltrations within the tumor and (F) corresponding quantification results. (G) Representative flow cytometric plots of DC maturation in lymphonodus. (H) TNF-α and IFN-γ concentrations in mouse sera before and 7 days after the OXA/R837/ALG treatment. (I) PDL1 expression on tumor cells and PD1 expression on TILs after the OXA/R837/ALG treatment and (J) the corresponding quantification of PDL1- and PD1-specific fluorescence signal intensities on different types of cells after various treatments are indicated. Data are means ± SEM. Statistical significance was calculated via two-tailed Student’s t test (F and J). ***P < 0.001. MFI, mean fluorescence intensity; a.u., arbitrary units.
Fig. 3
Fig. 3. Localized chemoimmunotherapy to achieve abscopal effect for CT26 colon tumors.
(A) Schematic to show the use of drug composition containing OXA/R837/anti-PDL1/ALG for treatment of CT26 colon tumor model. (B and C) Tumor growth curves (B) and body weight (C) of CT26 tumor–bearing mice after different treatments indicated. (D) Schematic illustration of localized chemoimmunotherapy to inhibit the tumor growth at distant sites. (E and F) Tumor growth curves of primary tumors (E) and distant tumors (F) of mice after various treatments indicated. (G) Body weight of mice after various treatments indicated. (H) Representative flow cytometric plots showing different groups of T cells in secondary tumors. (I to K) Proportions of tumor-infiltrating CD3+ T cells, CD8+ killer T cells, and CD4+ T cells according to data in (H). (L) CD8+ CTL:Treg ratios in the distant tumors. Statistical significance was calculated via two-tailed Student’s t test (I to L). ***P < 0.001. Photo credit (A): Yu Chao, Soochow University.
Fig. 4
Fig. 4. Long-term immune memory effect after localized chemoimmunotherapy.
(A) Schematic illustration to evaluate the immune memory effect after localized chemoimmunotherapy to treat CT26 tumors with DOX/R837/anti-PDL1/ALG or OXA/R837/ALG together with intravenously injected anti-PDL1. (B to D) Tumor growth curves (B), percent survival (C), and average body weights (D) of different groups of mice after various treatments, as indicated (n = 5). (E) Proportions of TEM in the spleen analyzed by flow cytometry (gated on CD3+CD8+ T cells) at day 60, right before rechallenging mice with secondary tumors. (F and G) Cytokine levels including IFN-γ (F) and TNF-α (G) in sera from mice isolated 5 days after mice were rechallenged with secondary tumors. Statistical significance was calculated via two-tailed Student’s t test (E to G). **P < 0.01; ***P < 0.001.
Fig. 5
Fig. 5. Localized chemoimmunotherapy to treat orthotopic breast tumors.
(A) Schematic to show using DOX-containing drug composite to treat 4T1 breast tumor models. Tumor growth curves (B) and body weight (C) of mice bearing subcutaneous 4T1 tumors after different treatments indicated. (D) Schematic illustration of localized chemoimmunotherapy to inhibit spontaneous tumor metastases in the orthotopic 4T1 breast tumor model. (E) Survival of mice bearing orthotopic fLuc-4 T1 breast tumors with spontaneous metastases after various treatments applied on their primary breast tumors (n = 10 per group). (F) In vivo bioluminescence images to track the spreading and growth of tumor cells after various treatments applied on their primary orthotopic tumors. Photo credit (A): Yu Chao, Soochow University.
Fig. 6
Fig. 6. Localized chemoimmunotherapy to treat orthotopic brain tumors.
(A) Schematic illustration of localized chemoimmunotherapy to treat the orthotopic brain tumor model. (B) Survival of mice bearing orthotopic brain tumors after various treatments indicated (n = 10 per group). (C and D) Cytokine levels including IFN-γ (C) and TNF-α (D) in sera from mice isolated 5 days after the treatment. (E) Tumor slices of brains from different groups of mice after various treatments indicated. (F and G) Number of CD4+ and CD8+ cells per tumor slice according to data in (E) and (F). (H) CD8+ to CD4+ ratio in tumor slice. (I) Schematic illustration of evaluating the immune memory effect after localized chemoimmunotherapy. (J and K) Tumor growth curves (J) and survival data (K) of different groups of mice after various treatments applied on day 0 to eliminate their orthotopic brain tumors (n = 5). The same type of tumor cells was subcutaneously inoculated on those mice on day 60. Statistical significance was calculated via two-tailed Student’s t test (C, D, and F to H). **P < 0.01; ***P < 0.001.
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