專題討論5:腫瘤治療與診斷新進展

S5-1
癌症免疫治療的最新發展與未來趨勢
林永昌教授
林口長庚醫院血液腫瘤科

  Inadequate to elicit a T cell response to cancer cell is a hallmark for tumor immune escape. Strategies to overcome this obstacle have been suggested more than a century. Majority of them have failed to demonstrate meaningful anti-tumor effect except for specific type of cancers, such as cytokines therapy or tumor infiltrating T cell therapy for malignant melanoma. In recent year, the immune checkpoint blockade has shown a huge step forward in this field.
   The major progress in tumor immunotherapy involved in the regulating CD28/CTLA-4 co-stimulatory receptors and PD-1/PDL-1 axis on activated T cells. Both were named as "immune-checkpoint" for their role in immune response is as "brake" to avoid overt immune response that may hurt host. Upon cognate antigen activation, majority of effector T cells will increasingly express such molecules, the effector functions will attenuated and eventually go into apoptosis. CTLA-4 is highly expressed in drained lymph node and mediated inhibitory signaling to suppress effector function; PD-1 is preferentiality expressed in tumor infiltrating T cells. PD-1 positive T cell will be eradicated if the tumor or tumor microenvironment express PDL-1/PDL-2 through oncogenic pathway or as consequence of Th1 response. In human, the major breakthrough was first demonstrated in anti-CTLA4 (ipilimumab, BMS/Ono) melanoma. The first trial was used in patients with previously treated advanced melanoma. The results were a big surprise that a significant portion of patients achieved a durable response. In fact, the recent follow-up study showed that for 17% 4846 patients receiving ipilimumab remains response beyond 7 years and no more relapse to date. The next products,PD-1/PDL-1 block ademolecules, was really hit the world. The clinical activity of PD-1 blockade was proven superior to anti-CTLA4 in terms of response rate and survivals. Other than melanoma, PDL-1 blockade have shown a quit broad clinical activity across various types of cancers, namely, lung cancer, renal cell carcinoma, Hodgkin’s lymphoma, urothelial carcinoma, SCC of head and neck, and more. This is never seen in human history that a single class of agent can exhibits such broad ranges of anti-tumor activities. Up to day, the list of authority approved labeling indications are still Increasing. The clinical us of PD-1/PDL-1 blockade has moved from salvage therapy to frontline therapy even being tested in adjuvant setting. To date, at least in several types of cancers that PD-1/PDL-1 blockade have been shown superior activity as compared with traditional chemotherapy in 2nd line. In the next few years, we will witness a growing number of cancer survivors rescued from a disease that we never be able to cure before.
   The step of tumor immunotherapy is nowadays a huge forward to human being, but would not be the final victory. In fact, we are far from success. Other than melanoma, patients that would benefit from immune checkpoint remain few to be optimistic. We are eager to explore how we can raise the digit of cure (or long-term control) rate, what population of patient would benefit from immunotherapy? We know that an 'inflamed" tumor could be the prerequisite for effective immune check-point blockade since enriched effector T cells in tumor microenvironment is the key for effective treatment. Therefore, strategies to make tumor more immunogenic might be employ to this clinical scenario. The growing knowledge in tumor immune response has provided various strategies to help us to improve immunotherapy response or to identify the potential "inflamed" tumors. Currently, the combination strategies, including dual blockade with both anti-CTLA4, and PD-1, combination with chemotherapy, radiotherapy or targeted therapy were under extensive investigation. Novel molecules engaged in tumor immune response are emerging. The PDL-1 expression, for example, in cancer cells or tumor-infiltrating lymphocyte was found to correlate with treatment response and was used as criteria for clinical patient selection, but the results are inconsistent. Currently, the searches for validate biomarkers for predicting treatment is an area of active research. Precision medicine for cancer immunotherapy is one of the futures.
   Today, I am going to discuss the current progress of immune checkpoint blockade, the strategy of combination therapy and the potential or ongoing markers for patient selection. I will propose the future development of immune oncology. We are optimistic that the dream of conquering cancer is coming true