Pushing Past the Blockade: Advancements in T Cell-Based Cancer Immunotherapies

Abstract

Successful cancer immunotherapies rely on a replete and functional immune compartment. Within the immune compartment, T cells are often the effector arm of immune-based strategies due to their potent cytotoxic capabilities. However, many tumors have evolved a variety of mechanisms to evade T cell-mediated killing. Thus, while many T cell-based immunotherapies, such as immune checkpoint inhibition (ICI) and chimeric antigen receptor (CAR) T cells, have achieved considerable success in some solid cancers and hematological malignancies, these therapies often fail in solid tumors due to tumor-imposed T cell dysfunctions. These dysfunctional mechanisms broadly include reduced T cell access into and identification of tumors, as well as an overall immunosuppressive tumor microenvironment that elicits T cell exhaustion. Therefore, novel, rational approaches are necessary to overcome the barriers to T cell function elicited by solid tumors. In this review, we will provide an overview of conventional immunotherapeutic strategies and the various barriers to T cell anti-tumor function encountered in solid tumors that lead to resistance. We will also explore a sampling of emerging strategies specifically aimed to bypass these tumor-imposed boundaries to T cell-based immunotherapies.

Oncolytic Viruses as an Adjunct to Immune Checkpoint Inhibition

“…This is an improvement from previous response rates with ipilimumab monotherapy (11%) and T-VEC monotherapy (26%) [20]. Other possible combinatorial therapies with OVT include PD-L1 and PD-1 inhibitors [21]. As OVTs like T-VEC specifically attract T-cells to the tumor microenvironment and upregulate tumor expression of PD-L1, for example, combining T-VEC with pembrolizumab offers a mechanism to enhance treatment response of an already effective therapy [22].…”

Coordinated single-cell tumor microenvironment dynamics reinforce pancreatic cancer subtype

“…Importantly, combination therapies that target TME mediators are being investigated to expand treatment options beyond cytotoxic agents 86 – 88 . This is in part due to the increasing knowledge of the cancer ecosystem and improved methods for high-resolution molecular data acquisition of patient tissues and model systems.…”

Boosting Checkpoint Immunotherapy with Biomimetic Nanodrug Delivery Systems

“…(TAMs). [53] Taking advantage of that, Kang et al have designed T cell membrane-coated NPs that could scavenge immunosuppressive molecules and reinvigorate CTLs via PD-1 protein modified on T cell membrane-coated NPs and antitumor drugs encapsulated within poly(lactic-co-glycolic acid) (PLGA). [54] Macrophages have typical features of tumor tropism and the ability to penetrate the endothelial barrier.…”