Anti-PD-(L)1/CTLA-4 checkpoint inhibitors (CPIs) have revolutionized the standard of care treatment paradigm in a variety of cancers. First approved in melanoma, anti-PD-(L)1 CPIs are currently indicated for numerous oncology indications including lung tumors, head and neck cancer, Hodgkin’s lymphoma, renal cell carcinoma, hepatocellular carcinoma, bladder, colorectal, and gastric cancer. This list is expected to expand progressively as CPIs continue to demonstrate clinical benefit in other oncology indications both as a single agent as well as in combination with anti-CTLA-4 CPI or chemotherapeutics.

Despite generating deep responses and durable remissions, the incidence of CPI-resistant cases is increasing as more cancer patients are being treated with CPIs. Currently, except for the anti-CTLA-4 Yervoy (ipilimumab), all the remaining marketed CPIs are targeting PD-1 or PD-L1, meaning that upon progression on a particular anti-PD-(L)1 CPI, a patient would not derive benefit from other anti-PD-(L)1 CPIs as they all target the same signaling mechanism. The clinical success of anti-PD-(L)1 CPIs in multiple tumor types and the resulting substantial financial gains prompted clinical development of numerous other “me too” anti-PD-(L)1 CPIs as they promise a safe route to approval and marketing based on the precedents. However, therapy resistance is common and a major unmet need in oncology and relapsed/refractory (r/r) cancers are much more difficult to treat compared to treatment-naïve counterparts. It is therefore critical that novel CPIs with diverse mechanisms of action are developed in order to maintain back-up treatment options upon disease progression on CPIs and challenge r/r tumors as effectively as possible.

Promising initial readouts for potential therapeutic approaches capable of reversing resistance to PD-1 inhibition were presented in this year’s AACR meeting. To this end, in a Phase Ib clinical trial, the combination of CMP-001, a Toll-like receptor 9 (TLR9) agonist with the anti-PD1 Keytruda (pembrolizumab) was highly active in a cohort of 69 patients with advanced melanoma who progressed on prior anti-PD-1. CMP-001 is a 30-mer native DNA oligonucleotide in a virus-like particle that leads to activation of dendritic cells, macrophages, and natural killer T cells, which are important components of the innate immunity against invading pathogens as well as instrumental in activating the components of the adaptive immunity such as cytotoxic T cells (CTLs).

The combination treatment therefore aims to mobilize simultaneously both innate and adaptive immune responses against more recalcitrant tumors. Notably, in this Phase Ib trial where 71% of the participants had previously received Keytruda and 58% reported progressive disease as their best response to prior PD-1 based therapy, the combination resulted in durable ongoing responses lasting longer than 84 weeks in some patients and an objective response rate (ORR) of 22%, which included 2 complete remissions. Of note, despite intratumoral injection of CMP-001, tumor regressions in injected as well as non-injected target lesions suggest a systemic effect.

In addition, increased PD-L1 expression and influx of CTLs were detected in tumor biopsies, indicating that the combination regimen was able to make the initially PD-1 resistant tumors more visible to the immune system. Despite the small sample size of the study and having been conducted in melanoma patients only, this approach is not tumor specific and may be applicable to other oncology indications. More importantly, it provides a proof-of-concept for combination strategies that target both innate and adaptive immunity and yet another testament to the power of an alert immune system in fighting cancer.

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GlobalData (2017). PharmaFocus: Visual Analysis of Immuno-Oncology Development and Opportunities, August 2017, GDHC009PFR.

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