31 In solid tumors, data are much scarcer, with two clinical trials that came out in 2020 in colorectal and pancreatic cancer. This has been recently seen in multiple myeloma 30 or in chronic lymphocytic leukemia. The majority of clinical studies addressing the CXCL12-CXCR4 axis have tackled hematological malignancies, where the neutralization of the CXCL12 gradient displaces malignant cells from the protected environment of the bone marrow towards the blood stream, where they are more susceptible to chemotherapy-mediated cell death. 27 28 More recent data from inhibition of the CXCL12 receptor CXCR4 showed alleviation of desmoplasia, increased T-lymphocyte infiltration and an improved immunotherapeutic effect in a murine model of metastatic breast cancer. In mouse models, inhibition of chemokine (C-X-C motif) receptor 4 (CXCR4), a CXCL12 receptor, led to the promotion of T-cell accumulation and synergistic effects with checkpoint inhibition, leading to cancer regression. Here, chemokine (C-X-C motif) ligand 12 (CXCL12) plays an important role. Animal experiments showed that immunosuppression can manifest as exclusion of T cells from tumor regions. 22вЂ“25 Immunosuppression and inflammation are key parameters 26 and modulation of these is a main aim of new approaches. 20 21 The composition of the different populations of immune cells and their corresponding cytokines and chemokines-which reflect immune cell presence and activity-shape the local microenvironment and the subsequent clinical course.

15вЂ“18 While the vast majority of research still focuses on the tumor microenvironment in primary lesions, 19 the role of infiltrating immune cells in metastases of CRC is also well established. The local immune infiltration (especially in CRC) influences the clinical course of the disease. 14 In this setting, the development of more complex interventions into the immune landscape requires detailed knowledge of the interactions of relevant players and their response to interventions. Advanced metastatic disease typically exhibits liver metastases next to other distant metastases. 5 9 For patients with stage IV disease and limited therapeutic options and a 5-year survival of 11%вЂ“14.2% in metastatic colorectal cancer (CRC) 10 11 and of 2.9% in pancreatic cancer 12 and particularly in case of a significant disease burden, 13 there is a tremendously high medical need for novel therapeutic options. Especially for microsatellite stable colorectal and pancreatic cancer, immunotherapy has thus far been ineffective. 6вЂ“8ДЇor the majority of patients with solid tumors, no effective immunotherapy strategy is yet available.

2вЂ“5 These approaches act on the complex interactions in the tumor microenvironment, as was shown recently in macrophage-targeted immunotherapies. Combinatorial approaches target the stromal compartment of solid tumors, resulting in migration of effector cells. 1 However, it has been recognized that the presence and reactivity of effector cells significantly affect the efficacy of immunotherapies. Their predominant mode of action is the activation of the adaptive immune system via checkpoint inhibition. In recent years, immunotherapy has changed the therapeutic landscape for solid tumors dramatically, with the approval of new drugs in many indications within a remarkably short period.

Stage plot pro 2.9 5 serial