Combination therapy: Future directions of immunotherapy in small cell lung cancer

Abstract

Small cell lung cancer (SCLC), an aggressive and devastating malignancy, is characterized by rapid growth and early metastasis. Although most patients respond to first-line chemotherapy, the majority of patients rapidly relapse and have a relatively poor prognosis. Fortunately, immunotherapy, mainly including antibodies that target the cytotoxic T lymphocyte antigen-4 (CTLA-4), checkpoints programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) to block immune regulatory checkpoints on tumor cells, immune cells, fibroblasts cells and endothelial cells, has achieved the milestone in several solid tumors, such as melanoma and non-small-cell lung carcinomas (NSCLC). In recent years, immunotherapy has made progress in the treatment of patients with SCLC, while its response rate is relatively low to monotherapy. Interestingly, the combination of immunotherapy with other therapy, such as chemotherapy, radiotherapy, and targeted therapy, preliminarily achieve greater therapeutic effects for treating SCLC. Combining different immunotherapy drugs may act synergistically because of the complementary effects of the two immune checkpoint pathways (CTLA-4 and PD-1/PD-L1 pathways). The incorporation of chemoradiotherapy in immunotherapy may augment antitumor immune responses because chemoradiotherapy can enhance tumor cell immunogenicity by rapidly inducing tumor lysis and releasing tumor antigens. In addition, since immunotherapy drugs and the molecular targets drugs act on different targets and cells, the combination of these drugs may achieve greater therapeutic effects in the treatment of SCLC. In this review, we focused on the completed and ongoing trials of the combination therapy for immunotherapy of SCLC to find out the rational combination strategies which may improve the outcomes for SCLC.

Clinical Activity and Safety of Anlotinib Combined with PD-1 Blockades for Patients with Previously Treated Small Cell Lung Cancer

“… 7 ORR of PD-1 blockades monotherapy was approximately <20% regardless of PD-L1 expression. 13 The overall response of anlotinib plus PD-1 blockades in our study suggested the potentially synergistic action for cancer therapy, which was in accordance with the conclusion observed in patients with hepatocellular carcinoma who were treated with atezolizumab plus bevacizumab combination therapy. 15 Interestingly, a recent study initiated by Fan et al performed a multicenter phase II clinical trial to identify the efficacy and safety of camrelizumab (PD-1 blockade) plus apatinib (another antiangiogenic targeted drug) in ES-SCLC.…”

“… 12 Consequently, more effective combination treatment regarding immunotherapy was needed to prolong the survival for patients with SCLC urgently. 13 …”

Immune Check Point Inhibitors and Immune-Related Adverse Events in Small Cell Lung Cancer

“…However, the findings still need to be assessed in large samples. Nevertheless, compared with single chemotherapy, PD-L1 inhibitor with chemotherapy for SCLC patients presented beneficial OS (A et al, 2019) ( 40 ), and there is increasing evidence that shows that combination therapy, such as combined with chemotherapy, radiotherapy, and other targeted therapy, may overcome the low response to ICI among SCLC patients ( 38 , 41 , 42 ).…”

Case Report: Intra-Tumoral Vaccinations of Quadrivalent HPV-L1 Peptide Vaccine With Topical TLR-7 Agonist Following Recurrence: Complete Resolution of HPV-HR-Associated Gynecologic Squamous Cell Carcinomas in Two Patients

“…This leads to the release, uptake, and processing of neoantigens followed by transport to regional lymph nodes. Importantly, the radiation-induced neoantigens are only present on cancer cells [14,15]. These tumor-specific antigens allow immune targeting and cross-presentation facilitating the recognition of the radiated tumors heterogeneous mutations producing a sort of personalized "in-situ vaccine."…”

“…These tumor-specific antigens allow immune targeting and cross-presentation facilitating the recognition of the radiated tumors heterogeneous mutations producing a sort of personalized "in-situ vaccine." [3,12,14] There is the possibility that the HPV-L1 vaccine which was injected throughout the tumor to account for genetic heterogeneity may have had an effect in attracting local macrophage, NK, and dendritic cells (Figure 2). Moreover, we cannot completely exclude the contribution of the trauma from repeated "needling" of the tumor, which may have added to the inflammatory responses.…”