Subverting the adaptive immune resistance mechanism to improve clinical responses to immune checkpoint blockade therapy

Abstract Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase (IDO/TDO) inhibitors.

Download Full-text

Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients?

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_240837 ◽

2019 ◽

pp. 147-164 ◽

Cited By ~ 103

Author(s):

Charlene M. Fares ◽

Eliezer M. Van Allen ◽

Charles G. Drake ◽

James P. Allison ◽

Siwen Hu-Lieskovan

Keyword(s):

Immune Checkpoint ◽

Acquired Resistance ◽

Resistance Mechanisms ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Mechanisms Of Resistance ◽

Primary Resistance ◽

Wide Range ◽

Clinical Responses ◽

Tumor Types

The emergence of immune checkpoint blockade therapies over the last decade has transformed cancer treatment in a wide range of tumor types. Unprecedented and durable clinical responses in difficult-to-treat cancer histologies have been observed. However, despite these promising long-term responses, the majority of patients fail to respond to immune checkpoint blockade, demonstrating primary resistance. Additionally, many of those who initially respond to treatment eventually experience relapse secondary to acquired resistance. Both primary and acquired resistance are a result of complex and constantly evolving interactions between cancer cells and the immune system. Many mechanisms of resistance have been characterized to date, and more continue to be uncovered. By elucidating and targeting mechanisms of resistance, treatments can be tailored to improve clinical outcomes. This review will discuss the landscape of immune checkpoint blockade response data, different resistance mechanisms, and potential therapeutic strategies to overcome resistance.

Download Full-text

Sufficiency of CD40 activation and immune checkpoint blockade for T cell priming and tumor immunity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1918971117 ◽

2020 ◽

Vol 117 (14) ◽

pp. 8022-8031 ◽

Cited By ~ 9

Author(s):

Alexander H. Morrison ◽

Mark S. Diamond ◽

Ceire A. Hay ◽

Katelyn T. Byrne ◽

Robert H. Vonderheide

Keyword(s):

T Cell ◽

Immune Checkpoint ◽

Tumor Model ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Cell Responses ◽

Adaptive Immune ◽

Cd40 Activation ◽

Polyfunctional T Cells ◽

Complete Tumor

Innate immune receptors such as toll-like receptors (TLRs) provide critical molecular links between innate cells and adaptive immune responses. Here, we studied the CD40 pathway as an alternative bridge between dendritic cells (DCs) and adaptive immunity in cancer. Using an experimental design free of chemo- or radiotherapy, we found CD40 activation with agonistic antibodies (⍺CD40) produced complete tumor regressions in a therapy-resistant pancreas cancer model, but only when combined with immune checkpoint blockade (ICB). This effect, unachievable with ICB alone, was independent of TLR, STING, or IFNAR pathways. Mechanistically, αCD40/ICB primed durable T cell responses, and efficacy required DCs and host expression of CD40. Moreover, ICB drove optimal generation of polyfunctional T cells in this “cold” tumor model, instead of rescuing T cell exhaustion. Thus, immunostimulation via αCD40 is sufficient to synergize with ICB for priming. Clinically, combination αCD40/ICB may extend efficacy in patients with “cold” and checkpoint-refractory tumors.

Download Full-text

IDO1 as a mechanism of adaptive immune resistance to anti-PD1 monotherapy in HNSCC.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.6053 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 6053-6053 ◽

Cited By ~ 2

Author(s):

Lori J Wirth ◽

Barbara Burtness ◽

Ranee Mehra ◽

Jessica Ruth Bauman ◽

Jina Lee ◽

...

Keyword(s):

Gene Expression ◽

Immune Checkpoint ◽

Cell Activity ◽

Response Rates ◽

Adaptive Immune ◽

Immune Resistance ◽

Resistance Pathway ◽

Checkpoint Molecule ◽

Clinical Responses ◽

Immune Related Genes

6053 Background: Patients with recurrent/metastatic human papillomavirus-associated head and neck squamous cell carcinoma (HPV-HNSCC) demonstrate improved response rates to anti-PD-1 blockade, which may be attributed to the inherent inflammation associated with the local expression of foreign, highly immunogenic viral antigens. However, these response rates are at best 25%, suggesting there may be immune resistance networks that are limiting clinical responses to anti-PD-1 therapy. To address this question, we investigated other potential immune checkpoint pathways that may be upregulated in PD-L1 expressing HPV-HNSCCs. Methods: Using a custom microarray of 59 immune-related genes, we compared the gene expression profile of laser-captured micro-dissected PD-L1 (+) and (-) immune fronts in HPV-HNSCCs. Gene expression was validated using quantitative PCR (qPCR) and protein expression geographically localized using quantitative multiplex biomarker imaging in a separate cohort of HPV-HNSCCs. Furthermore, we assayed pre- and post-treatment biopsies from anti-PD-1 treated patients and correlated gene expression with clinical responses. Results: Of the immune-related genes, IDO1 was increased 65-fold in 10 PD-L1(+) as compared to 5 PD-L1(-) HPV-HNSCCs (p = 0.004). qPCR confirmed upregulated expression of IDO1 and quantitative immunofluorescence demonstrated that PD-L1 and IDO1 geographically co-localized within the tumor microenvironment in a validation cohort of 25 HPV-HNSCC patients. In anti-PD1 treated patients, IDO1 expression increased up to two-fold and correlated with disease progression in HNSCC patients. Conclusions: IDO1 is an immune checkpoint molecule that modulates T cell activity through the depletion of L-tryptophan. We propose that IDO1 is an adaptive immune resistance pathway to anti-PD-1 monotherapy. The results provide rationale for combinatorial therapies targeting the IDO1 and PD-1:PD-L1 networks in HNSCC patients.

Download Full-text

Systemic immunological biomarkers of clinical responses in immune checkpoint blockade therapies

Lung Cancer Management ◽

10.2217/lmt-2018-0014 ◽

2018 ◽

Vol 7 (3) ◽

pp. LMT07 ◽

Cited By ~ 1

Author(s):

Hugo Arasanz ◽

Miren Zuazo ◽

Ruth Vera ◽

Grazyna Kochan ◽

David Escors

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Clinical Responses

Download Full-text

Treatment Progress of Immune Checkpoint Blockade Therapy for Glioblastoma

Frontiers in Immunology ◽

10.3389/fimmu.2020.592612 ◽

2020 ◽

Vol 11 ◽

Author(s):

Na Zhang ◽

Li Wei ◽

Meng Ye ◽

Chunsheng Kang ◽

Hua You

Keyword(s):

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Resistance Mechanism ◽

Primary Brain Tumor ◽

Immune Checkpoint Blockade ◽

Brain Parenchyma ◽

Checkpoint Blockade ◽

Research Progress ◽

Recent Success

Glioblastoma (GBM) is a highly malignant and aggressive primary brain tumor mostly prevalent in adults and is associated with a very poor prognosis. Moreover, only a few effective treatment regimens are available due to their rapid invasion of the brain parenchyma and resistance to conventional therapy. However, the fast development of cancer immunotherapy and the remarkable survival benefit from immunotherapy in several extracranial tumor types have recently paved the way for numerous interventional studies involving GBM patients. The recent success of checkpoint blockade therapy, targeting immunoinhibitory proteins such as programmed cell death protein-1 and/or cytotoxic T lymphocyte-associated antigen-4, has initiated a paradigm shift in clinical and preclinical investigations, and the use of immunotherapy for solid tumors, which would be a potential breakthrough in the field of drug therapy for the GBM treatment. However clinical trial showed limited benefits for GBM patients. The main reason is drug resistance. This review summarizes the clinical research progress of immune checkpoint molecules and inhibitors, introduces the current research status of immune checkpoint inhibitors in the field of GBM, analyzes the molecular resistance mechanism of checkpoint blockade therapy, proposes corresponding re-sensitive strategies, and describes a reference for the design and development of subsequent clinical studies on immunotherapy for GBM.

Download Full-text

Bifunctional PD-1 × αCD3 × αCD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia

Blood ◽

10.1182/blood-2018-05-849802 ◽

2018 ◽

Vol 132 (23) ◽

pp. 2484-2494 ◽

Cited By ~ 20

Author(s):

Monika Herrmann ◽

Christina Krupka ◽

Katrin Deiser ◽

Bettina Brauchle ◽

Anetta Marcinek ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

T Cell ◽

T Cell Activation ◽

Immune Checkpoint ◽

Myeloid Leukemia ◽

Cell Activation ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Adaptive Immune ◽

Acute Myeloid

Abstract The CD33-targeting bispecific T-cell engager (BiTE) AMG 330 proved to be highly efficient in mediating cytolysis of acute myeloid leukemia (AML) cells in vitro and in mouse models. Yet, T-cell activation is correlated with upregulation of programmed cell death-ligand 1 (PD-L1) and other inhibitory checkpoints on AML cells that confer adaptive immune resistance. PD-1 and PD-L1 blocking agents may counteract T-cell dysfunction, however, at the expense of broadly distributed immune-related adverse events (irAEs). We developed a bifunctional checkpoint inhibitory T cell–engaging (CiTE) antibody that combines T-cell redirection to CD33 on AML cells with locally restricted immune checkpoint blockade. This is accomplished by fusing the extracellular domain of PD-1 (PD-1ex), which naturally holds a low affinity to PD-L1, to an αCD3.αCD33 BiTE-like scaffold. By a synergistic effect of checkpoint blockade and avidity-dependent binding, the PD-1ex attachment increases T-cell activation (3.3-fold elevation of interferon-γ) and leads to efficient and highly selective cytotoxicity against CD33+PD-L1+ cell lines (50% effective concentration = 2.3-26.9 pM) as well as patient-derived AML cells (n = 8). In a murine xenograft model, the CiTE induces complete AML eradication without initial signs of irAEs as measured by body weight loss. We conclude that our molecule preferentially targets AML cells, whereas high-affinity blockers, such as clinically approved anticancer agents, also address PD-L1+ non-AML cells. By combining the high efficacy of T-cell engagers with immune checkpoint blockade in a single molecule, we expect to minimize irAEs associated with the systemic application of immune checkpoint inhibitors and suggest high therapeutic potential, particularly for patients with relapsed/ refractory AML.

Download Full-text