The Treatment of Advanced Lung Cancer With Dribbles Antigen by Targeting

Malignant tumor has become the leading cause of death in humans, and the number one killer in malignant tumor is the lung cancer. Intensifying environmental pollution comes with rising of the incidence of lung cancer and the high mortality,what's the worst that the 5-year survival rate is only about 15%, accounting for first place in the malignant tumors, Exploiting for novel antitumor technology and products comes to arrest growing attention of the governments and businesses because of the uneffectively curbing of tumor threat to people's life and health on conventional three treatments (surgery, radiotherapy and chemotherapy). Biological and immunotherapy was voted to one of the ten big breakthrough in 2013 by Science magazine, and considered as a new development direction for cancer treatment in the 21st century.

The existing immune treatment mainly includes: adoptive immune therapy, tumor vaccine therapy, immune checkpoint-antibody therapy and other auxiliary therapy, and the adoptive immunotherapy was researched and developeded former in addition the most mature treatment among these therapies. The adoptive immunotherapy has been carried out in many units primarily is the autologous DC - CIK immunotherapy,which called the Dendritic cells (Dendritic cells, DC) and Cytokine Induced Killer cells (Cytokine Induced Killer, CIK) immunotherapy. The principle of this technology is: separating of monocytes and lymphocytes of human peripheral blood, then ugmentated and activated by a variety of cytokines in vitro (e.g., IFN - gamma, IL - 1, IL - 2, anti - CD3 mAb) to a mixed lymphocyte with antigen presenting and broad-spectrum function of killing tumor cells. The amplifying activated DC-CIK intravenous back to patients, releasing of active substances such as CIK cells perforin,and grain enzyme B to tumor cells after combining with the tumor cells in the body, which dissolves the tumor cells.Meanwhile the secreting of a variety of cytokines, such as IL - 2, IFN - gamma and TNF alpha, improves the body's immune function, and gives the role of anti-tumor function.

Existing literature report and our previous study in biological treatment center showed that good safety, small side effects and good tolerance for the vast majority of patients. In curative effect, the current report reveals DC-CIK technology has a good curative effect maidly on leukemia, lymphoma, ovarian cancer, stomach cancer, etc., except for lung cancer.It could because of the complex lung cancer tumor antigen,or weak tumor specific T cell response. How to improve the effectiveness of the presented lung cancer antigen and stimulate stronger tumor specific T cell response needs to be addressed in improving the curative effect of the lung cancer immunotherapy.

In recent years checkpoint point antibody therapy has a breakthrough in tumor immunotherapy, including CTLA-4, PD - 1 and PD - L1. a number of clinical studies revealed the therapy of PD - 1 and PD - L1 antibody for advanced NSCLC, especially in lung squamous carcinoma has good treatment effect, and the disease objective response rate achieve 10-23%. Autologous DC/CIK therapy has been widely carried out in domestic,and has a good security proved by many clinical practice.As the lack of effective tumor antigen, there are no large randomized, double-blind study confirm its function in extending patient survival and preventing tumor progression so far. Some hospitals adopted the tumor cell lysis solution or single molecule protein peptide/DC united CIK technology, which means to load tumor cell lysis or single molecule protein peptide as a tumor antigen to DC unite with in vitro induced CIK at the same time.When compared to CIK therapy alone, the unit therapy can not only non-specificly damage tumor,but also induce the body to produce tumor-specific immune response.However most of the tumor antigens contained in tumor cell lysis are longevity protein that cannot be effectively intaken by DC,leading to limited effective antigen presented by DC to T lymphocyte. In addition, the tumor antigen longevity protein can exist for a long time in the natural growth of tumor cells, and can be recognized by the patients for its own organization,therefore immune tolerance inhibites the immune response affecting the effect of killing tumor. Single molecule protein polypeptide only induce specific immune response to a single or a few tumor antigen, not the mutatd tumor antigen,resulting in escape of tumor. We need to develop new cell treatments because of autologous DC/CIK therapy can not produce effective immune response ,for providing a new aiternative candidate to unite checkpoint antibody therapy in the future.

Recently, Dr Hu Hong - Ming's team put forward an innovative cancer treatment strategy: using of autophagy role to capture tumor antigen for preparation of tumor vaccine. In this strategy, the blocking proteasome activity of in vitro cultured tumor cells dealed with Bortezomib (proteasome inhibitors) causes enrichment of short-lived protein (SLiPs) and misfolded proteins (DRiPs) in autophagosome,called DRibbles corpuscle. Tumor vaccine maded from collecting these DRibbles corpuscle preparation as, also known as the DRibble vaccine.Our early studies have suggested that the DRibble tumor vaccines are more powerful than the tumor cell vaccine, because the whole tumor cell vaccine does not contain easily degradated short-lived proteins which cannot be cross presented to DC efficiently. These short-lived protein avoid being degradated by the proteasome in the DRibble vaccine, and packaged into autophagosome vesicles with double membrane structure. These vesicles contain endogenous risk signaling molecules (such as HSP90, HMGB1, etc.), can effectively trigger the congenital immune response. Therefore, when co-culture with once DRibble vaccine,DC can effectively intake DRibble vaccine and presenting tumor related antigen to the DC surface, combining with MHC molecules to activate T cells, resulting in the immune response. Compared with whole lung cancer vaccine, DRibble lung cancer vaccines can provide a wider range of tumor associated antigen, make the body no longer keep the tolerance for lack of cross presented, which can cause strong immune response. Dr Hu Hong Ming's team have also found that allogeneic Dribble can induce equally effective immune response compare with autologous tumor cells DRibble vaccine and tumor regression, the result has been confirmed in multiple tumor models. Due to the lack of classic MHC molecules,DRibble vaccine proteins can be rapidly degradated by DC, and allogeneic DRibble vaccine would not induce adverse effects due to the induction of allograft immune response, remaindering it's safety and efficacy.