COMBINED EFFECTS OF SELECTIVE PHOTOTHERMAL THERAPY AND IMMUNOADJUVANT AGAINST STAGE IV BREAST CANCER

Metastasis to distant sites is a severe treatment challenge and a major cause of death for breast cancer patients.Laser immunotherapy(LIT)is a novel technique,combining a selective photothermal therapy with local application of glycated chitosan,a potent immunoadjuvant.The pre-clinical studies of LIT have shown its unique characteristics in generating specific antitumor immunity.The clinical application of LIT in the treatment of melanoma patients has achieved preliminary success.Recently,LIT has been used to treat late-stage breast cancer patients.Here we report for the first time the clinical results of this combination therapy in breast cancer patients.The LIT treatment procedures are presented and the medical history of two stage Ⅳ breast cancer patients is reviewed.Most of the breast cancer lesions and the metastasis of lung and brain disappeared after repeated treatments of LIT.One patient achieved complete response;the other achieved partial response at the time of this report.Although there is still a long way for LIT to become a standard modality for breast cancer treatment,the results of this study indicated its promising future.

ANTI-TUMOR RESPONSES INDUCED BY LASER IRRADIATION AND IMMUNOLOGICAL STIMULATION USING A MOUSE MAMMARY TUMOR MODEL

Anti-tunor immunological response induced by local intervention is ideal for treatment of metastatic tumors.Laser immunot herapy was developed to synergize photot hermal interaction with immunological stimulation for cancer treatment.Using an infrared laser,indocyanine green(ICG,as a light abeorbing agent),and glycated chitosan(GC,as an immunostimulant),.laser imm unot herapy has resulted in tumor suppression and anti-tumor responses in pre-clinical as well as clinical studies.To further understand the mechanism of laser immunotherapy,the efects of laser and GC treatment without specifc enhancement of laser absorption were studied.Passive adoptive immunity transfer was perfomed using splenocytes as immune cells.Spleen cells harvested from tumor-bearing mice treated by laser+GC provided 60%immunity in naive recipients.Furthermore,cytotoxicity and TNF-ar secretion by splenocytes from treated mice also indicated that laser+GC induced immunity was tumor-specific.The high level of infiltrating T cells in tumors after laser+GC treatment furt her confirned a specific anti-tumor immune response.Therefore,laser+GC could prove to be a promisi ng selective local trea tment modality that induces a systemic anti-tumor response,with appropriate laser parameters and GC doses.

Immune modulations of the tumor microenvironment in response to phototherapy

The tumor microenvironment(TME)promotes pro-tumor and anti-infammatory metabolismsand suppresses the host immune system.It prevents immune cells from fighting against cancereffectively,resulting in limited efficacy of many current cancer treatment modalities.Differenttherapies aim to overcome the immunosuppressive TME by combining various approaches tosynergize their effects for enhanced antitumor activity and augmented stimulation of the im-mune system.Immunotherapy has become a major therapeutic strategy because it unleashes thepower of the immune system by activating,enhancing,and directing immune responses to pre-vent,control,and eliminate cancer.Phototherapy uses light iradiation to induce tumor celldeath through photothermal,photochemical,and photo-immunological interactions.Photo-therapy induces tumor immunogenic cell death,which is a precursor and enhancer for anti-tumorimmunity.However,phototherapy alone has limited effects on long-term and systemic anti-tumor immune responses.Phototherapy can be combined with immunotherapy to improve thetumoricidal effect by killing target tumor cells,enhancing immune cell infiltration in tumors,andrewiring pathways in the TME from antinfammatory to pro-inflammatory.Phototherapy-enhanced immunotherapy triggers effective cooperation bet ween innate and adaptive immunities,specifically targeting the tumor cells,whether they are localized or distant.Herein,the successes and limitations of phototherapy combined with other cancer treatmentmodalities will be discussed.Specifically,we will review the symergistic effects of phototherapy combined with different cancer therapies on tumor elimination and remodeling of the immuno-suppressive TME.Overll,phototherapy,in combination with other therapeutic modalities,canestablish anti-tumor pro-infammatory phenotypes in activated tumor-infiltrating T cells andB cells and activate systemic anti-tumor immune responses.

Photonics immunotherapy-A novel strategy for cancer treatment

Photonics immunotherapy is a novel cancer treatment strategy that combines local phototherapy and immunotherapy.Phototherapy is a noninvasive or minimally invasive therapeutic strategy for local treatment of cancer,which can destroy tumor cells and release tumor antigens,inducing an in situ antitumor immune response.Immunotherapy,including the use of antibodies,vaccines,immunoadjuvants and cytokines,when combined with phototherapy,could bring a synergistic effect to stimulate a host immune response that effectuates a long-term antitumor immunity.This review will focus on the development of photonics immunotherapy and its systemic antitumor immunological effects.

Anti-tumor response induced by immunologically modified carbon nanotubes and laser irradiation using rat mammary tumor model

The ideal treatment modality for metastatic cancer would be a local treatment that can destroy primary tumors while inducing an effective systemic anti-tumor response.To this end,we de-veloped laser immunotherapy,combining photothermal laser application with an immunoadju-vant for the treatment of metastatic cancer.Additionally,to enhance the selective photothermal effect,we integrated light-absorbing nanomaterials into this innovative treatment.Specifically,we developed an immunologically modified carbon nanotube combining single-walled carbon nanotubes(SWNTs)with the immunoadjuvant glycated chitosan(GC).To determine the ef-fectiveness of laser iradiation,a series of experiments were performed using two different irra-diation durations-5 and 10 min.Rats were inoculated with DMBA-4 cancer cells,a metastatic cancer cell line.The treatment group of rats receiving laser irradiation for 10 min had a 50%long-term survival rate without residual primary or metastatic tumnors.The treatment group of rats receiving laser irradiation for 5 min had no long-term survivors;all rats died with multiple metastases at several distant sites.Therefore,Laser+SWNT-GC treatment with 10 min of laser irradiation proved to be efective at reducing tumor size and inducing long-term anti-tumor immunity.

SINGLE CELL IMAGING OF BAX TRANSLOCATION DURING APOPTOSIS INDUCED BY PHOTOFRIN-PDT

Apoptosis is an important cellular event that plays a key role in the therapy of many diseases.The mechanism of the initiation and regulation of photodynamic therapy(PDT)–induced apoptosis is complex.Our previous study found that Photofrin was localized primarily in mitochondria,the primary targets of Photofrin-PDT.The key role of Bax in the mitochondria-mediated apoptosis has been demonstrated in many systems.In order to determine the role of Bax in the mitochondrion-mediated apoptosis induced by Photofrin-PDT,we used the GFP-Bax plasmid to monitor the dynamics of Bax activation after PDT treatment.With laser scanning confocal microscopy,we found that Bax did not translocate from the cytosol to mitochondria when the mitochondrial membrane potential(∆Ψm)disappeared,measured by TMRM.Thus,for Photofrin-PDT,the commitment to cell death is independent of Bax activation.

Interstitial photoacoustic technique and computational simulation for temperature distribution and tissue optical properties in interstitial laser photothermal interaction

Interstitial laser immunotherapy(ILIT)is designed to use photothermal and immunological inter-actions for treatment of metastatic cancers.The photothermal ffect is crucial in inducing anti-tumorimmune responses in the host.Tissue temperature and tssue optical properties are important factorsin this process.In this study,a device combining interstitial photoacoustic(PA)technique andinterstitial laser photothermal interaction is proposed.Together with computational simulation,thisdevice was designed to determine temperature distributions and tissue optical properties during lasertreatment.Experiments were performed usinger-ivoFporcine liver tissue.Our results demonstratedthat interstitial PA signal amplitude was linearly dependent on tisue temperature in the tempera-ture ranges of 20-60℃,as wll as 65-80℃,with a dfferent slope,due to the change of tissue opticalproperties.Using the directly measured temperature in the tissue around the interstitial optical fiberdiffusion tip for calibration,the theoretical temperature distribution predicted by the bioheatequation was used to extract optical properties of tssue.Finally,the three-dimensional temperature distribution was simulated to guide tumor destruction and immunological stimulation,Thus,thisnovel device and method could be used for monitoring and controlling ILIT for cancer treatment.