Bifunctional Blockade: A Novel Immunotherapy Approach for Cervical Cancer

In this issue of Clinical Cancer Research, Feng and colleagues report on the safety and efficacy of a bifunctional fusion protein targeting PD-L1 and TGFβ in a phase I expansion cohort of advanced cervical squamous cell carcinoma (SCC; ref. 1). In this study, the investigators demonstrate that SHR-1701 has clinical activity in immunotherapy-naive patients, with an objective response rate (ORR) of 15.6% and a median duration of response that has not yet been reached. Notably, the ORR was similar regardless of PD-L1 expression.

Despite some advances in the management of metastatic cervical cancer, the outcomes of these patients remain poor, even with the incorporation of PD-1/PD-L1 blockade. In the recently published KEYNOTE-826 study, the median overall survival for patients treated with pembrolizumab plus chemotherapy with or without bevacizumab was 24 months (2). Single-agent PD-1/PD-L1 blockade has demonstrated modest but durable benefits in advanced cervical cancer (3, 4), and pembrolizumab monotherapy is approved for use in PD-L1–positive tumors after progression on platinum-based chemotherapy. There remain many unanswered questions regarding mechanisms of resistance, best combinatorial strategies, and an ongoing search for prognostic biomarkers beyond PD-L1 expression in this patient population.

The authors’ work builds on prior studies of combinatorial immuno-oncology agents in advanced or recurrent cervical SCC. CheckMate-358 examined several dosing levels and schedules of nivolumab plus the anti–CTLA-4 antibody ipilimumab; in patients who had not received prior systemic therapies, the ORR ranged from 32% to 46%; clinical benefit was seen regardless of PD-L1 status (5). Similarly, the combination of balstilimab (anti–PD-1) and zalifrelimab (anti–CTLA-4) for patients with recurrent or metastatic disease resulted in an ORR of 22%; PD-L1 expression enriched for responders, but responses were seen in PD-L1–negative patients (6).

In studies such as these, the goal is to enhance the antitumor immune response by addressing immunosuppressive factors beyond the PD-1/PD-L1 axis (7, 8). In solid tumors, the tumor microenvironment (TME) plays a key role in resistance to immune checkpoint inhibitors, including immunosuppressive populations of regulatory T cells (Treg), tumor-associated macrophages, and myeloid-derived suppressor cells. Moreover, cytokines such as IL10, and TGFβ have been implicated in diminished host antitumor response leading to tumor immune escape (9, 10).

TGFβ plays a particularly important role in the TME due to its twin functions in both normal cellular processes and immunosuppression (Fig. 1). It is an important inhibitor of cell proliferation with roles in apoptosis, angiogenesis, and wound healing. In early neoplastic processes, TGFβ aids in tumor suppression, but can later drive tumor progression and metastasis by disrupting host immune response and inducing tumor epithelial-to-mesenchymal transformation (11). Targeting of TGFβ thereby offers a strategy to remodel the TME and invigorate host response and is a leading candidate for drug development. Its impact has been investigated in both preclinical and clinical studies with small-molecule inhibitors of the TGFβ receptor and anti-TGFβ monoclonal antibodies. In contrast to the excellent preclinical results, TGFβ blockade has been disappointing in clinical trials, with single-agent activity only noted in small subsets of patients (12, 13). Thus, there has remained a need for an alternative approach to inhibit TGFβ in the TME.

SHR-1701, a bifunctional fusion protein composed of a monoclonal antibody against PD-1 fused with the extracellular membrane of TGFβ receptor II, represents a novel strategy to overcome these proposed mechanisms of immune resistance through targeting nonredundant pathways. In preclinical animal models of murine CMT167 lung tumor cells, SHR-1701 demonstrated both successful inhibition of the TGF-β/TGF-β receptor pathway and preservation of downstream pAkt pathway of PD-1/PD-L1, thus overcoming acquired resistance to anti–PD-1 antibodies in mice with impaired lymphocyte recovery. These findings support the utility of a bifunctional protein in cancer previously exposed to chemotherapy and associated imbalances in CD8⁺ T/Treg cells (14).

Other bifunctional fusion proteins include bintrafusp alfa (M7824), which also consists of a TGFβ ‘trap’ and IgG1 antibody blocking PD-L1, and the anti–TGFβ/PD-L1 bispecific antibody YM101 (15, 16). In preclinical trials, bintrafusp alfa demonstrated similar ability as SHR-1701 to decrease Treg activity and reverse the epithelial-to-mesenchymal transformation, thereby improving chemo-sensitivity and augmenting host T-cell response (17). Its clinical activity and safety have been investigated in human papillomavirus–associated cancers (18), and in patients with advanced/recurrent cervical cancer, bintrafusp alfa demonstrated an ORR of 28.2% (19). Importantly, preclinical data for SHR-1701, bintrafusp alfa, and YM101 all demonstrate that the bifunctionality of these proteins increase the concentration of TGFβ receptor II in the TME through binding PD-L1. This offers a clear rationale for a single bifunctional molecule versus the use of an anti–PD-L1 monoclonal antibody in combination with the use of an TGFβ inhibitor while also reducing the potential adverse effects of the systemic delivery of a TGFβ antagonist.

Notably, in this study, there were no differences in response observed between patients with and without PD-L1 expression. This finding is consistent with previously published data for bintrafusp alfa in SCC of the head and neck (15), and is in contrast to the FDA approval of pembrolizumab, which is limited to those patients with PD-L1–positive disease. While PD-L1 expression lacks both sensitivity and specificity as a biomarker for response to immune checkpoint inhibitors, these data suggest that a bispecific approach may offer an alternative therapeutic tactic for patients with PD-L1–negative disease. The authors also attempt to define a new prognostic biomarker through the measurement of pSMAD2. SMAD proteins play a role in the downstream activation of TGF-B signaling; an elevated pSMAD2 level may predict those with higher response to inhibition of the SMAD-dependent TGFβ pathway. Although limited by the small sample size, the suggestion of an association is hypotheis generating and warrants further study.

The development of novel immuno-oncology agents, alone or in combination with other systemic, targeted, or biologic agents, represents an exciting step forward in the treatment of cervical cancer. The authors report that SHR-1701 will be investigated in a phase III study comparing its use versus placebo in combination with upfront chemotherapy ± bevacizumab; similar phase III studies are ongoing with BCD-100 (anti–PD-1) and atezolizumab (anti–PD-L1; NCT03912415, NCT03556839). AK104, an anti–PD-1 and anti–CTLA-4 bispecific antibody, already has demonstrated impressive clinical activity and reasonable safety when combined with standard chemotherapy in the upfront setting (20).

In conclusion, SHR-1701 demonstrates antitumor activity and safety in patients with recurrent or metastatic cervical cancer after platinum-based chemotherapy. This clinical space is evolving quickly, with the incorporation of single and potentially dual checkpoint blockade into the upfront treatment of advanced or recurrent disease. This trial may serve as proof of principle that the TGFβ pathway may be successfully targeted, and thus a therapeutic target moving forward.

C.F. Friedman reports personal fees from Seagen and Bristol-Myers Squibb and other support from Genentech and Merck outside the submitted work as well as financial support to institution from Merck, Bristol-Myers Squibb, AstraZeneca, Daiichi, and Seagen. No disclosures were reported by the other author.

The authors are supported in part by a Cancer Center Support Grant of the NIH/NCI (grant no. P30CA008748).