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11. The use of histotripsy as intratumoral immunotherapy beyond tissue ablation—the rationale for exploring the immune effects of histotripsy.

Author

Osada, Takuya, Jiang, Xiaoning, Zhao, Yuhang, Chen, Mengyue, Kreager, Benjamin C., Wu, Huaiyu, Kim, Howuk, Ren, Jun, Snyder, Joshua, Zhong, Pei, Morse, Michael A., and Lyerly, H. Kim

Subjects
*HIGH-intensity focused ultrasound, *IMMUNOTHERAPY, *CANCER patient care, *IMMUNE response, *ANIMAL models in research, *LIVER tumors
Abstract

Mechanical high-intensity focused ultrasound (M-HIFU), which includes histotripsy, is a non-ionizing, non-thermal ablation technology that can be delivered by noninvasive methods. Because acoustic cavitation is the primary mechanism of tissue disruption, histotripsy is distinct from the conventional HIFU techniques resulting in hyperthermia and thermal injury. Phase I human trials have shown the initial safety and efficacy of histotripsy in treating patients with malignant liver tumors. In addition to tissue ablation, a promising benefit of M-HIFU has been stimulating a local and systemic antitumor immune response in preclinical models and potentially in the Phase I trial. Preclinical studies combining systemic immune therapies appear promising, but clinical studies of combinations have been complicated by systemic toxicities. Consequently, combining M-HIFU with systemic immunotherapy has been demonstrated in preclinical models and may be testing in future clinical studies. An additional alternative is to combine intratumoral M-HIFU and immunotherapy using microcatheter-placed devices to deliver both M-HIFU and immunotherapy intratumorally. The promise of M-HIFU as a component of anti-cancer therapy is promising, but as forms of HIFU are tested in preclinical and clinical studies, investigators should report not only the parameters of the energy delivered but also details of the preclinical models to enable analysis of the immune responses. Ultimately, as clinical trials continue, clinical responses and immune analysis of patients undergoing M-HIFU including forms of histotripsy will provide opportunities to optimize clinical responses and to optimize application and scheduling of M-HIFU in the context of the multi-modality care of the cancer patient. [ABSTRACT FROM AUTHOR]

Published
2023
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12. A Non-Invasive Deep Photoablation Technique to Inhibit DCIS Progression and Induce Antitumor Immunity.

Author

Kaneko, Kensuke, Nagata, Hiroshi, Yang, Xiao-Yi, Ginzel, Joshua, Hartman, Zachary, Everitt, Jeffrey, Hughes, Philip, Haystead, Timothy, Morse, Michael, Lyerly, Herbert Kim, and Osada, Takuya

Subjects
BREAST cancer treatment, DISEASE progression, BIOLOGICAL models, IN vitro studies, IN vivo studies, IMMUNE checkpoint inhibitors, CANCER invasiveness, ANIMAL experimentation, HEAT shock proteins, DUCTAL carcinoma, TREATMENT effectiveness, IMMUNITY, SURVIVAL analysis (Biometry), PROGRESSION-free survival, CELL lines, COMBINED modality therapy, CARCINOMA in situ, MICE, EVALUATION
Abstract

Simple Summary: Fewer than half of ductal carcinoma in situ (DCIS) cases progress to invasive breast cancer (BC); however, most are treated surgically, which raises a concern of overtreatment. Novel approaches to the management of DCIS that do not rely on surgery are warranted. In this study, we assessed the efficacy of heat shock protein 90 (Hsp90)-targeted photodynamic therapy (HS201-PDT) as a novel alternative treatment to target DCIS and prevent progression to invasive BC. The preventive application of HS201-PDT to the mammary glands of spontaneous murine DCIS models significantly improved disease-free survival. Enhancement of immune response with systemically administered anti-PD-L1 antibodies along with repeated HS201-PDT to mammary glands was effective even in a more aggressive DCIS model. Thus, HS201-PDT monotherapy or the combination with anti-PD-L1 antibodies is a promising strategy that could serve as an alternative treatment of DCIS to prevent progression to invasive BC. Ductal carcinoma in situ (DCIS) of the breast is often managed by lumpectomy and radiation or mastectomy, despite its indolent features. Effective non-invasive treatment strategies could reduce the morbidity of DCIS treatment. We have exploited the high heat shock protein 90 (HSP90) activity in premalignant and malignant breast disease to non-invasively detect and selectively ablate tumors using photodynamic therapy (PDT). PDT with the HSP90-targeting photosensitizer, HS201, can not only ablate invasive breast cancers (BCs) while sparing non-tumor tissue, but also induce antitumor immunity. We hypothesized that HS201-PDT would both non-invasively ablate DCIS and prevent progression to invasive BC. We tested in vitro selective uptake and photosensitivity of HS201 in DCIS cell lines compared to the non-selective parental verteporfin, and assessed in vivo antitumor efficacy in mammary fat pad and intraductal implantation models. Selective uptake of HS201 enabled treatment of intraductal lesions while minimizing toxicity to non-tumor tissue. The in vivo activity of HS201-PDT was also tested in female MMTV-neu mice prior to the development of spontaneous invasive BC. Mice aged 5 months were administered HS201, and their mammary glands were exposed to laser light. HS201-PDT delayed the emergence of invasive BC, significantly prolonged disease-free survival (DFS) (p = 0.0328) and tended to improve overall survival compared to the no-treatment control (p = 0.0872). Systemic administration of anti-PD-L1 was combined with HS201-PDT and was tested in a more aggressive spontaneous tumor model, HER2delta16 transgenic mice. A single PDT dose combined with anti-PD-L1 improved DFS compared to the no-treatment control, which was significantly improved with repetitive HS201-PDT given with anti-PD-L1 (p = 0.0319). In conclusion, a non-invasive, skin- and tissue-sparing PDT strategy in combination with anti-PD-L1 antibodies effectively prevented malignant progression of DCIS to invasive BC. This non-invasive treatment strategy of DCIS may be safe and effective, while providing an option to reduce the morbidity of current conventional treatment for patients with DCIS. Clinical testing of HS201 is currently underway. [ABSTRACT FROM AUTHOR]

Published
2022
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20. An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer

Author

Morse, Michael A., Hobeika, Amy C., Osada, Takuya, Berglund, Peter, Hubby, Bolyn, Negri, Sarah, Niedzwiecki, Donna, Devi, Gayathri R., Burnett, Bruce K., Clay, Timothy M., Smith, Jonathan, and Lyerly, H. Kim

Subjects
Antigen-antibody reactions -- Research -- Methods, Immune response -- Observations -- Research -- Methods, Immunotherapy -- Methods -- Research, Virus-vector relationships -- Research, Cancer vaccines -- Dosage and administration -- Research, CEA (Oncology) -- Properties -- Methods -- Research, Health care industry
Abstract

Therapeutic anticancer vaccines are designed to boost patients' immune responses to tumors. One approach is to use a viral vector to deliver antigen to in situ DCs, which then activate tumor-specific T cell and antibody responses. However, vector-specific neutralizing antibodies and suppressive cell populations such as Tregs remain great challenges to the efficacy of this approach. We report here that an alphavirus vector, packaged in virus-like replicon particles (VRP) and capable of efficiently infecting DCs, could be repeatedly administered to patients with metastatic cancer expressing the tumor antigen carcinoembryonic antigen (CEA) and that it overcame high titers of neutralizing antibodies and elevated Treg levels to induce clinically relevant CEA-specific T cell and antibody responses. The CEA-specific antibodies mediated antibody-dependent cellular cytotoxicity against tumor cells from human colorectal cancer metastases. In addition, patients with CEA-specific T cell responses exhibited longer overall survival. These data suggest that VRP-based vectors can overcome the presence of neutralizing antibodies to break tolerance to self antigen and may be clinically useful for immunotherapy in the setting of tumor-induced immunosuppression., Introduction Efficacious therapeutic anticancer vaccines are now becoming a reality, but a number of challenges remain. More efficient platforms for delivering antigen to in situ DCs, critical for activation of [...]

Published
2010
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42. Targeting Id1 and Id3 inhibits peritoneal metastasis of gastric cancer

Author

Tsuchiya, Takeshi, Okaji, Yurai, Tsuno, Nelson H., Sakurai, Daisuke, Tsuchiya, Naoyuki, Kawai, Kazushige, Yazawa, Kentaro, Asakage, Masahiro, Yamada, Jun, Yoneyama, Satomi, Kitayama, Joji, Osada, Takuya, Watanabe, Toshiaki, Tokunaga, Katsushi, Takahashi, Koki, and Nagawa, Hirokazu

Published
2005

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