Emerging strategies for combination checkpoint modulators in cancer immunotherapy

Abstract

Current immune checkpoint-modulating agents have demonstrated clinical efficacy in certain tumor types, particularly those with a high burden of tumor-specific neoantigens, high tumor-mutational burden, and abundant tumor-infiltrating T cells. However, these tumors often stop responding, with signs of T cells exhaustion, decreased T cell effector function, and upregulated inhibitory checkpoints. To enhance antitumor immunity and rescue exhausted T cells, newer inhibitory and stimulatory checkpoint modulators are being tested as monotherapy or in combination with approved checkpoint inhibitors. In contrast, tumors with low tumor-mutational burden, low neoantigen burden, and a paucity of T cells are immunologically "cold," and therefore first require the addition of agents to facilitate the induction of T cells into tumors. Cold tumors also often recruit immunosuppressive cell subsets, including regulatory T cells, myeloid-derived suppressor cells, and macrophages, and secrete immunosuppressive soluble cytokines, chemokines, and metabolites. To unleash an optimal antitumor immune response, combinatorial therapeutics that combine immune checkpoints with other modalities, such as vaccines, are being developed. From current preclinical data, it appears that combinatorial strategies will provide robust and durable responses in patients with immunologically cold cancers.

Figure 1. Resistance mechanisms to current checkpoint inhibitors.

Factors that contribute to resistance to checkpoint inhibitors may be primary, adaptive, or acquired. In the lymph node, T cells are subject to precise regulation by both stimulatory (4-1BB, OX40, GITR) and inhibitory (PD-1, LAG3, TIM3, TIGIT, CTLA-4) checkpoints. The upregulation of inhibitory checkpoints may lead to T cell exhaustion. Furthermore, once T cells traffic to the TME, Teffs may be subject to multiple immunosuppressive signals by both immune cell subsets, such as M2-polarized tumor-associated macrophages (TAMs), Tregs, and MDSCs, and soluble mediators, including cytokines, such as TGF-β, IL-10, various chemokines, VEGF, adenosine, and IDO1. Tumors may also recruit a stromal compartment consisting of fibroblasts and other cell types. Furthermore, as a mechanism of adaptive resistance, IFN may itself cause PD-L1 to become upregulated on tumor cells. Finally, genomic alterations within tumor cells may lead to resistance. These include increased oncogenic signaling through the MAPK pathway, loss of PTEN expression with enhanced PI3K signaling, and altered β-catenin, causing constitutive WNT signaling.

Figure 2. Checkpoints modulate T cell and antigen-presenting cell interactions.

Either antagonist (red) or agonist (green) antibodies are currently under clinical testing based on promising preclinical data. Shown are the antibodies’ interactions with ligand(s). Antibodies against PD-1 and CTLA-4 are FDA approved. The remaining antibodies are in clinical trials.

Figure 3. Combinatorial therapy of checkpoint modulators with other anticancer modalities.

(A) Immunologically hot and cold tumors differ in neoantigen burden. Hot tumors just need checkpoint inhibitors or combinations of checkpoint inhibitors and/or checkpoint agonist antibodies to optimize T cell function. However, in addition to checkpoint modulation, naturally cold tumors require T cells to be first primed and then to traffic to the tumor tissue. (B) Several strategies exist to induce priming of T cells and/or enhance antigen expression, such as vaccines, oncolytic viruses, chemotherapy, and radiation. Polarized dendritic cells then traffic to the lymph node and activate T cells, a process that is regulated precisely by stimulatory (e.g., OX40, GITR, 4-1BB) and inhibitory checkpoints (e.g., PD-1, LAG-3, TIM3, VISTA), which can enhance or inhibit T cell responses, respectively. These checkpoints can be modulated by their respective antibodies that are currently being tested clinically. Many cold tumors also require reprogramming of other immune subsets in the TME. Tumors recruit immunosuppressive cells, such as Tregs, MDSCs, and M2-polarized macrophages, which can be modified via various strategies. The action of soluble mediators, such as adenosine, IDO, cytokines (TGF-β), and chemokines, can also be modulated.