Using Combination therapy to overcome diverse challenges of Immune Checkpoint Inhibitors treatment

Abstract

Immune checkpoint inhibitors (ICIs) have heralded a new era in immunotherapy, representing a pivotal breakthrough in cancer treatment. Their impact is profound, with ICIs standing as some of the most prescribed anticancer therapies today. Notably, their ability to induce long-term remission even after treatment cessation provides genuine hope for achieving durable cures. However, despite these strides, challenges persist in the landscape of oncology, including resistance phenomena, immune-related adverse events, and suboptimal response rates. In response to these challenges, combination therapy emerges as a promising approach, poised to enhance treatment outcomes and address limitations inherent to single-agent ICI therapy. By synergistically targeting multiple pathways, combination therapy holds the potential to augment therapeutic efficacy while mitigating toxicity and impeding the emergence of resistance mechanisms. Understanding the intricacies underlying resistance development and adverse events is paramount in devising novel and refined combination strategies. A timeline showing FDA approvals of ICIs combination is shown in Figure 1. This review aims to provide a comprehensive and up-to-date examples of different combined therapy strategies that can be used to overcome various challenges regarding ICI treatment. Through the exploration of innovative therapeutic combinations, we aim to provide clinicians and researchers with actionable knowledge to optimize patient outcomes and propel the field of immuno-oncology forward.

Figure 1

Timeline of FDA-approved combination immunotherapies as of April 2024. The timeline shows the first times the FDA approved a certain type of combination and the indication for which the combination was approved. The data is based on the FDA database. https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications. Created with BioRender.com.

Figure 2

Different drug combinations with ICI can be used for different purposes. Panel 1. Resistance. 1A. The main mechanisms that can lead to the development of ICI-resistance are low levels of neoantigens presentation, suppressive components in the TME, and T cell exhaustion,,. 1B. The combination of pembrolizumab with pemetrexed and platinum compounds can be used to overcome ICI-resistance. Platinum compounds induce dendritic cells recruitment and maturation and increase antigen presentation-. 1C. Pembrolizumab and anti VEGF such as Lenvatinib. Lenvatinib can decrease the levels of PD-L1 expression and reduce the infiltration of suppressor cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells,. Panel 2. Severe irAEs. 2A. The main mechanisms that can lead to the development of irAEs are activation of self-reactive T cells, shared antigens between cancer cells, and increased production of inflammatory cytokines and chemokines-. 2B. The combination of ipilimumab and anti-TNFα agent such as infliximab was shown to be effective for treating corticosteroid-refractory ICI-related colitis. In addition, adalimumab was successful in ameliorating the severity of ICI-related joints inflammation. 2C. AntI-CD20 agents such as rituximab were effective in ameliorating ICI-related irAEs that are associated with the detection of autoantibodies such as encephalitis. Panel 3. Low response rate. 3A. There is an ongoing effort to find new strategies to enhance the anti-tumor response since most cancer patients will not achieve the treatment goals. One of these strategies is to gain an additive or synergistic effect by using combination therapy. 3B. Combining ICIs with radiotherapy has the potential to improve the treatment outcome. Following radiotherapy, some patients may express somatic mutations that generate neoantigens which have the potential to increase the immune responses,. 3C. Another significant motivation to explore new CT with ICIs is to increase the range of indications for additional types of cancer, such TNBC. The combination of trastuzumab (an anti-HER-2 mAb) with pembrolizumab has been evaluated in clinical trials in patients with advanced or metastatic HER positive breast cancer that is resistant to trastuzumab. The data gathered from this trial showed promising therapeutic outcomes including 15% response rates in PD-L1-positive tumors with 13% 12-month PFS. Created with BioRender.com.