Xiaosong Li

Chitin, Chitosan, and Glycated Chitosan Regulate Immune Responses: The Novel Adjuvants for Cancer Vaccine

With the development of cancer immunotherapy, cancer vaccine has become a novel modality for cancer treatment, and the important role of adjuvant has been realized recently. Chitin, chitosan, and their derivatives have shown their advantages as adjuvants for cancer vaccine. In this paper, the adjuvant properties of chitin and chitosan were discussed, and some detailed information about glycated chitosan and chitosan nanoparticles was also presented to illustrate the trend for future development.

InCVAX - A novel strategy for treatment of late-stage, metastatic cancers through photoimmunotherapy induced tumor-specific immunity

A novel, promising potential cancer vaccine strategy was proposed to use a two-injection procedure for solid tumors to prompt the immune system to identify and systemically eliminate primary and metastatic cancers. The two-injection procedure consists of local photothermal application on a selected tumor intended to liberate whole cell tumor antigens, followed by a local injection of an immunoadjuvant that consists of a semi-synthetic functionalized glucosamine polymer, N-dihydro-galacto-chitosan (GC), which is intended to activate antigen presenting cells and facilitate an increased uptake of tumor antigens. This strategy is thus proposed as an in situ autologous cancer vaccine (inCVAX) that may activate antigen presenting cells and expose them to tumor antigens in situ, with the intention of inducing a systemic tumor specific T-cell response. Here, the development of inCVAX for the treatment of metastatic cancers in the past decades is systematically reviewed. The antitumor immune responses of local photothermal treatment and immunological stimulation with GC are also discussed. This treatment approach is also commonly referred to as laser immunotherapy (LIT).

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

Anti-tumor immunological response induced by local intervention is ideal for treatment of metastatic tumors. Laser immunotherapy was developed to synergize photothermal interaction with immunological stimulation for cancer treatment. Using an infrared laser, indocyanine green (ICG, as a light absorbing agent), and glycated chitosan (GC, as an immunostimulant), laser immunotherapy 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 effects of laser and GC treatment without specific enhancement of laser absorption were studied. Passive adoptive immunity transfer was performed 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-α secretion by splenocytes from treated mice also indicated that laser + G induced immunity was tumor-specific. The high level of infiltrating T cells in tumors after laser + GC treatment further confirmed a specific anti-tumor immune response. Therefore, laser + GC could prove to be a promising selective local treatment modality that induces a systemic anti-tumor response, with appropriate laser parameters and GC doses.

Laser Immunotherapy: Concept, Possible Mechanism, Clinical Applications, and Recent Experimental Results

Laser immunotherapy (LIT) is an in situ autologous cancer vaccine (inCVAX) that induces a systemic immune responses through a local intervention. The effect of LIT depends on two major interactions: a selective photothermal interaction and an active immunological stimulation. The selective photothermal interaction can help release tumor antigens, which can stimulate specific antitumor immunity in the host. The elevated expression of heat-shock protein and the local application of immunoadjuvant further enhance the immune responses. The safety and effectiveness of LIT have been tested in preclinical studies and in preliminary clinical trials. Tumor samples from breast cancer patients treated by LIT were analyzed using histochemical methods. Preliminary results showed a change in T cells after LIT treatment, indicating strong induced immune responses. LIT may be proven to be a feasible treatment modality for metastatic cancers.

Influence of drug-light-interval on photodynamic therapy of port wine stains—Simulation and validation of mathematic models

OBJECTIVESnWe established mathematical models of photodynamic therapy (PDT) on port wine stains (PWS) to observe the effect of drug-light-interval (DLI) and optimize light dose.nnnMATERIALS AND METHODSnThe mathematical simulations included determining (1) the distribution of laser light by Monte Carlo model, (2) the change of photosensitizer concentration in PWS vessels by a pharmacokinetics equation, (3) the change of photosensitizer distribution in tissue outside the vessels by a diffuse equation and photobleaching equation, and (4) the change of tissue oxygen concentration by the Ficks law with a consideration of the oxygen consumption during PDT. The concentration of singlet oxygen in the tissue model was calculated by the finite difference method. To validate those models, a PWS lesion of the same patient was divided into two areas and subjected to different DLIs and treated with different energy density. The color of lesion was assessed 8-12 weeks later.nnnRESULTSnThe simulation indicated the singlet oxygen concentration of the second treatment area (DLI=40 min) was lower than that of the first treatment area (DLI=0 min). However, it would be increased to a level similar to that of the first treatment area if the light irradiation time of the second treatment area was prolonged from 40 min to 55 min. Clinical results were consistent with the results predicted by the mathematical models.nnnCONCLUSIONSnThe mathematical models established in this study are helpful to optimize clinical protocol.

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 developed laser immunotherapy, combining photothermal laser application with an immunoadjuvant 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 effectiveness of laser irradiation, a series of experiments were performed using two different irradiation 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 tumors. 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 effective at reducing tumor size and inducing long-term anti-tumor immunity.

Light distribution in intravascular low level laser therapy applying mathematical simulation: a comparative study.

Intravascular low level laser therapy (ILLLT) has been applied in the treatment of many diseases for about twenty years. However, much fundamental work has not been done on its dosimetry. The study was designed to compare the difference of light distribution during ILLLT between using flat end fiber and optical fiber coupled with cylindrical light diffuser. Light distribution of He-Ne laser was processed by Monte Carlo model. The laser output was 5 mW. The diameter of both optical fibers was 400 microm. Four tissue optical parameters were chosen for simulation. The results showed that optical parameters of blood are important to determine the distribution of laser energy. The highest power density could increase to over 5000 mW/cm2 using flat end fiber. And the laser energy was absorbed by the blood cells in very small area before the tip of flat end fiber. But when using optical fiber coupled with cylindrical light diffuser, the highest power density was about 100 mW/cm2. More volume of blood cells could be irradiated by laser light. In summary, optical fiber coupled with cylindrical light diffuser is superior to flat end fiber at the aspect of increasing the volume of irradiated blood and decreasing unwanted damage to blood cells during intravascular low level laser therapy.

Photothermal therapy combined with dinitrophenyl hapten for the treatment of late stage malignant melanoma

To evaluate the efficacy and safety of photothermal with dinitrophenyl hapten (DNP) for patients with malignant melanoma (MM), Patients with pathology confirmed stage III or IV MM were enrolled. Seventy-two patients were randomized into two groups, DNP alone group (n=36) and DNP plus photothermal therapy group (n=36). The results showed that the patients in the combination treatment group had longer median progression-free survival time (19.0m vs. 12.0m, p=0.007). No severe adverse events were observed in both groups. Thus, the combination of photothermal therapy and DNP maybe a new therapeutic strategy for patients with advanced MM.

Treatment of advanced melanoma with laser immunotherapy and ipilimumab

Immunotherapy has become a promising modality for melanoma, especially using checkpoint inhibitors, which revive suppressed T cells against the cancer. Such inhibitors should work better when combined with other treatments which could increase the number and quality of anti-tumor T cells. We treated one patient with advanced (stage IV) melanoma, using the combination of laser immunotherapy (LIT), a novel immunological approach for metastatic cancers that has been shown to stimulate adaptive immunity, and ipilimumab. The patient was treated with LIT, followed with one course of ipilimumab 3u2005months after the beginning of LIT. After LIT treatment, all treated cutaneous melanoma in head and neck cleared completely. After the application of ipilimumab, all the tumor nodules in the lungs decreased. The patient had remained tumor free for one year. While anecdotal, the responses seen in this patient support the hypothesis that laser immunotherapy increases the number and quality of anti-tumor T cells so that ipilimumab and other checkpoint inhibitors are more effective in enhancing the therapeutic effects. Picture: Schematic of treatment using laser immunotherapy and ipilimumab on a stage IV melanoma patient.

Influence of light irradiation modalities on light distribution in human whole blood

To compare the differences of the light distributions in blood with different light irradiation modalities, Monte Carlo simulation was applied. The light distribution of He-Ne laser (632.8nm) in human whole blood was simulated. The diameter of the optic fiber used was 400μm. We referred to the work done by other researchers to determine tissue optical parameters of blood. For the same output laser power of 5mW, our results showed that the highest power density could be more than 6000mW/cm2 using flat end optic fiber. But when using optical fiber coupled with cylindrical light diffuser (the length for light emission =3mm), the highest power density was less than 210mW/cm2. Increasing the length of light emission could further reduce the highest power density. In summary, the optical fiber coupled with cylindrical light diffuser is a good modality for in vivo light irradiation in whole blood, which can decrease the light intensity and make it more uniformed distributed in blood. It is of great importance to choose the suitable light emission length of optic fiber coupled with cylindrical light diffuser for clinical applications.