Next-generation immunotherapy for solid tumors: combination immunotherapy with crosstalk blockade of TGFβ and PD-1/PD-L1

ABSTRACT

Introduction

In solid tumor immunotherapy, less than 20% of patients respond to anti-programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) agents. The role of transforming growth factor β (TGFβ) in diverse immunity is well-established; however, systemic blockade of TGFβ is associated with toxicity. Accumulating evidence suggests the role of crosstalk between TGFβ and PD-1/PD-L1 pathways.

Areas covered

We focus on TGFβ and PD-1/PD-L1 signaling pathway crosstalk and the determinant role of TGFβ in the resistance of immune checkpoint blockade. We provide the rationale for combination anti-TGFβ and anti-PD-1/PD-L1 therapies for solid tumors and discuss the current status of dual blockade therapy in preclinical and clinical studies.

Expert opinion

The heterogeneity of tumor microenvironment across solid tumors complicates patient selection, treatment regimens, and response and toxicity assessment for investigation of dual blockade agents. However, clinical knowledge from single-agent studies provides infrastructure to translate dual blockade therapies. Dual TGFβ and PD-1/PD-L1 blockade results in enhanced T-cell infiltration into tumors, a primary requisite for successful immunotherapy. A bifunctional fusion protein specifically targets TGFβ in the tumor microenvironment, avoiding systemic toxicity, and prevents interaction of PD-1+ cytotoxic cells with PD-L1+ tumor cells.

KEYWORDS:

• Crosstalk
• dual blockade therapy
• PD-1
• PD-L1
• TGFβ

Article highlights

• PD-1/PD-L1-targeting monotherapies have achieved promising results in treating patients with selected solid tumors; efficacy is limited to less than 20% of patients, even in those who are responsive to therapy.

• In addition to suppressing anti-tumor immune responses, TGFβ plays a crucial role in ICB-based therapy.

• TGFβ and PD-1/PD-L1 signaling synergize each other in a positive feedback manner to impair the anti-tumor CTL response.

• Dual blockade TGFβ and PD-1/PD-PD-L1 therapy improves anti-tumor efficacy and has manageable treatment-related adverse events.

This box summarizes key points contained in the article.

Acknowledgments

We acknowledge excellent editorial assistance from Summer Koop of the MSK Thoracic Surgery Service.

Abbreviations

Transforming growth factor β (TGFβ); TGFβ-activated kinase 1 binding protein 1 (TAB1); TGFβ-activated kinase 1 (TAK1); nuclear factor-κB (NF-κB); TGFβ receptor (TGFβR); extracellular signal-regulated kinase (ERK); p38 mitogen-activated protein kinase (p38 MAPK); JUN N-terminal kinase (JNK); tumor necrosis (TNF); TNF receptor-associated factor (TRAF); Programmed cell death 1(PD-1); programmed cell death 1 ligand 1 (PD-L1); programmed cell death 1 ligand 2 (PD-L2); lymphocyte-specific protein tyrosine kinase (Lck); zeta-chain-associated protein kinase 70 (ZAP70); protein kinase C-theta (PKCθ); linker for activation of T cells (LAT); nuclear factor of activated T cells 1 (NFATc1); activator protein 1 (AP-1); T-box expressed in T cells (T-bet); B lymphocyte-induced maturation protein-1 (Blimp-1); nuclear factor kappa light chain enhancer of activated B cells (NF-κB); B-cell lymphoma (Bcl6); Forkhead box protein O1 (FoxO1); signal transducer and activator of transcription (STAT); interferon-stimulated gene factor 3 (ISGF3); interferons (IFNs); T-cell receptor (TCR); antisense oligonucleotides (AONs); treatment-related adverse events (TRAEs); anti-TGFβRII monoclonal antibody (IMC-TR1); Fc-γ receptor (FcγR); prostate-specific membrane antigen (PSMA); PD-1 nanobodies (αPD-1); glycoprotein A repetitions predominant (GARP); immune checkpoint blockade (ICB); cytotoxic T lymphocyte (CTL); PD-1 dominant negative receptor (PD1-DNR); tumor-infiltrating lymphocyte (TIL); lymphocytic choriomeningitis virus (LCMV); tumor immune microenvironment (TME); epithelial-mesenchymal transition (EMT); overall response rate (ORR)

Declaration of interest

PS Adusumilli declares research funding from ATARA Biotherapeutics; Scientific Advisory Board Member and Consultant for ATARA Biotherapeutics, Bayer, Carisma Therapeutics, Imugene, ImmPactBio, Johnston & Johnston, OutpaceBio; Patents, royalties and intellectual property on mesothelin-targeted CAR and other T-cell therapies, which have been licensed to ATARA Biotherapeutics, issued patent method for detection of cancer cells using virus, and pending patent applications on PD-1 dominant negative receptor, wireless pulse-oximetry device, and on an ex vivo malignant pleural effusion culture system.

Memorial Sloan Kettering Cancer Center (MSK) has licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics and has associated financial interests.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

PS Adusumilli’s laboratory work is supported by grants from the National Institutes of Health (P30 CA008748, R01 CA236615-01, R01 CA235667, and U01 CA214195), the U.S. Department of Defense (BC132124, LC160212, CA170630, CA180889, and CA200437), the Batishwa Fellowship, the Cycle for Survival fund, the Comedy vs Cancer Award, the DallePezze Foundation, the Derfner Foundation, the Esophageal Cancer Education Fund, the Geoffrey Beene Foundation, the Memorial Sloan Kettering Technology Development Fund, the Miner Fund for Mesothelioma Research, the Mr. William H. Goodwin and Alice Goodwin, the Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center. P.S.A.’s laboratory receives research support from ATARA Biotherapeutics.