**11.5 Avelumab**

In a Phase 1b JAVELIN trial, a human anti-PD-L1 IgG1 mab, Avelumab, was tested in patients with MBC [68] (**Table 3**). A total of 168 MBC previously treated patients were treated with avelumab monotherapy, including 58 TNBC patients. The confirmed ORR for the whole population was 3%, with 1 CR (complete response) and 4 PRs (partial responses). The ORR for TNBC patients was 5.2 percent. Furthermore, in both general population (16.7% vs. 1.6%) and in TNBC class (22.2% vs. 2.6%) patients with PD-L1 positive tumor-associated immune cells had a greater ORR than those with PD-L1 negative tumor-associated immune cells.

### **11.6 CTLA-4 inhibitors**

CTLA-4 inhibits T-cell activation by interacting with its target ligand, CD80 or CD86 [69, 70]. Monoclonal antibodies (mAbs) that block CTLA-4 have been demonstrated to augment T-cell activation and thereby enhance cancer cell death.

### **11.7 Tremelimumab**

A phase II open-label trial (NCT02527434) is evaluating the efficacy of Tremelimumab, a CTLA-4 inhibitor, in patients with advanced solid tumors such as TNBC (**Table 3**). While on treatment with tremelimumab, if the patient's develops progression in disease, they are given Durvalumab or a Durvalumab/Tremelimumab in combination. The objective response rate is the primary endpoint, with length of response, progression-free survival, and overall survival as secondary endpoints [71].

## **12. Drug repurposing an important aspect in immunotherapy regimen**

Despite the success of disease diagnosis in modern era, the recent developments and discovery of new drug is laborious, inefficient, time consuming process and costly process [72, 73]. Not only that most drugs face high failure rates in clinical trials [74]. To overcome these problems in drug discovery a strategy namely drug repurposing (also called drug reprofiling or repurposing) came into existence which works by identifying existing drugs and using them for new purposes [75]. Several strategies

*Integrating Immunotherapy with Chemotherapy: A New Approach to Drug Repurposing DOI: http://dx.doi.org/10.5772/intechopen.100183*

are being put to use in order to repurpose the existing drugs whether FDA approved or which are used under investigation. These include methods based on computational and non-computational strategies, also experimental based studies. However, the computational methods help in improved effectiveness in repurposing a drug. The computational methods help to select the effective candidate drugs before in-vitroexperiments [76]. Drug repurposing in breast cancer is considered an old weapon for new war. The immunotherapy approach in combination with chemotherapy is considered an important modality in TNBC treatment. As already discussed due to escape mechanisms in immunotherapy it is being combined with chemotherapy that repurposing the old school drugs for instance some FDA approved drugs like Anthracyclines and taxanes. Also these drugs are being repurposed to modulate the immune system response for better clinical outcome [74, 77]. For instance, cyclophosphamide that is an alkylating chemotherapeutic agent having well-built immunosuppressive activity and acts via cytotoxic or through immune enhancing mechanisms. However due to its high toxicity effects low-dose cyclophosphamide has been combined with immunotherapy options like immune checkpoint inhibitors, immune therapeutic agents including vaccines as well and it been tested and has shown better results in animal models [77]. Accordingly in this chapter we have provided a detailed account for the combination of immunotherapy with chemotherapy as an effective mechanism for drug repurposing that is using the different strategies to modulate existing drugs for efficient use.
