Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy

[D.ap]

Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy

Abstract
Combined PD-1 and CTLA-4-targeted immunotherapy with nivolumab and ipilimumab is effective against melanoma, renal cell carcinoma and non-small-cell lung cancer1,2,3. However, this comes at the cost of frequent, serious immune-related adverse events, necessitating a reduction in the recommended dose of ipilimumab that is given to patients4. In mice, co-treatment with surrogate anti-PD-1 and anti-CTLA-4 monoclonal antibodies is effective in transplantable cancer models, but also exacerbates autoimmune colitis. Here we show that treating mice with clinically available TNF inhibitors concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, improves anti-tumour efficacy. Notably, TNF is upregulated in the intestine of patients suffering from colitis after dual ipilimumab and nivolumab treatment. We created a model in which Rag2−/−Il2rg−/− mice were adoptively transferred with human peripheral blood mononuclear cells, causing graft-versus-host disease that was further exacerbated by ipilimumab and nivolumab treatment. When human colon cancer cells were xenografted into these mice, prophylactic blockade of human TNF improved colitis and hepatitis in xenografted mice, and moreover, immunotherapeutic control of xenografted tumours was retained. Our results provide clinically feasible strategies to dissociate efficacy and toxicity in the use of combined immune checkpoint blockade for cancer immunotherapy.


https://www.nature.com/articles/s41586-019-1162-y

tumor necrosis factor
If you have an immune system disease like rheumatoid arthritis (RA), you may have heard your doctor use the term TNF. It's shorthand for tumor necrosis factor, a protein in your body that causes inflammation and helps coordinate the process.

Aug 25, 2020
WebMD › rheumatoid-arthritis › ho...
Tumor Necrosis Factor (TNF): How Does It Cause Inflammation?

Soluble TNF-α is best known for its role in leading immune defenses to protect a localized area from invasion or injury but it is also involved in controlling whether target cells live or die. In general, TNF largely relies on TNFR1 for apoptosis and on TNFR2 for any function related to T-cell survival.Jun 1, 2014

www.ncbi.nlm.nih.gov › articles › P...
TNF-α, a good or bad factor in hematological diseases? - NCBI

[D.ap]

Fundamental Mechanisms of Immune Checkpoint Blockade Therapy



Abstract

Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge.

Significance: This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. Cancer Discov; 8(9); 1069–86. ©2018 AACR.

https://cancerdiscovery.aacrjournals.or ... /1069.full

[D.ap]

Introduction

Immune checkpoint blockade therapies are now FDA approved for the treatment of a broad range of tumor types (Table 1), with approval likely for additional indications in the near future. The realization of long-term durable responses in a subset of patients represents a transformative event. Since the 2011 FDA approval of ipilimumab (anti-CTLA4) for the treatment of metastatic melanoma, 5 additional checkpoint blockade therapies, all targeting the PD-1/PD-L1 axis, have been approved for the treatment of a broad range of tumor types. Additionally, ipilimumab plus nivolumab (anti–PD-1) combination therapy has been approved for the treatment of advanced melanoma with favorable outcomes compared with either monotherapy. However, as we look to the future and aspire to extend these remarkable responses to more patients and tumor types, many aspects of T-cell activation and the mechanisms of checkpoint blockade remain to be understood. Here, we review how the negative costimulatory molecules CTLA4 and PD-1 attenuate T-cell activation. We also discuss current dogma and recent conceptual advances related to the mechanisms of action of anti–PD-1 and anti-CTLA4 therapies in the context of antitumor immunity. These discussions highlight the importance of understanding the underlying fundamental biological phenomena for effective translational and clinical research. In the context of the current landscape of cancer immunotherapy, fully understanding how anti-CTLA4 and anti–PD-1 checkpoint blockade therapies work will be critical for effectively combining them with other immunotherapeutic, chemotherapeutic, and targeted approaches.

[D.ap]

Collapse inline
Table 1.
Summary of the tumor types for which immune checkpoint blockade therapies are FDA-approved
Tumor type Therapeutic agent FDA approval year
Melanoma Ipilimumab 2011
Melanoma Nivolumab 2014
Melanoma Pembrolizumab 2014
Non–small cell lung cancer Nivolumab 2015
Non–small cell lung cancer Pembrolizumab 2015
Melanoma (BRAF wild-type) Ipilimumab + nivolumab 2015
Melanoma (adjuvant) Ipilimumab 2015
Renal cell carcinoma Nivolumab 2015
Hodgkin lymphoma Nivolumab 2016
Urothelial carcinoma Atezolizumab 2016
Head and neck squamous cell carcinoma Nivolumab 2016
Head and neck squamous cell carcinoma Pembrolizumab 2016
Melanoma (any BRAF status) Ipilimumab + nivolumab 2016
Non–small cell lung cancer Atezolizumab 2016
Hodgkin lymphoma Pembrolizumab 2017
Merkel cell carcinoma Avelumab 2017
Urothelial carcinoma Avelumab 2017
Urothelial carcinoma Durvalumab 2017
Urothelial carcinoma Nivolumab 2017
Urothelial carcinoma Pembrolizumab 2017
MSI-high or MMR-deficient solid tumors of any histology Pembrolizumab 2017
MSI-high, MMR-deficient metastatic colorectal cancer Nivolumab 2017
Pediatric melanoma Ipilimumab 2017
Hepatocellular carcinoma Nivolumab 2017
Gastric and gastroesophageal carcinoma Pembrolizumab 2017
Non–small cell lung cancer Durvalumab 2018
Renal cell carcinoma Ipilimumab + nivolumab 2018
NOTE: A summary of the tumor indications, therapeutic agents, and year of FDA approval for immune checkpoint blockade therapies. FDA approval includes regular approval and accelerated approval granted as of May 2018. Ipilimumab is an anti-CTLA4 antibody. Nivolumab and pembrolizumab are anti–PD-1 antibodies. Atezolizumab, avelumab, and durvalumab are anti–PD-L1 antibodies. Tumor type reflects the indications for which treatment has been approved. Only the first FDA approval granted for each broad tissue type or indication for each therapeutic agent is noted. In cases where multiple therapies received approval for the same tumor type in the same year, agents are listed alphabetically.
Abbreviations: MSI, microsatellite instability; MMR, mismatch repair.

[D.ap]

Immunology The delivery of a 2nd signal from an antigen-presenting cell to a T cell, which rescues an activated T cell from anergy, allowing it to produce the lymphokines necessary for production of additional T cells.
medical-dictionary.thefreedictionary.com › ...
Costimulation | definition of Costimulation by Medical dictionary

Abstract. Negative costimulatory signals mediated via cell surface molecules such as CTLA-4 and programmed death 1 (PD-1) play a critical role in down-modulating immune responses and maintaining peripheral tolerance. However, their role in alloimmune responses remains unclear.Jun 1, 2005
J Immunol › content
Analysis of the Role of Negative T Cell Costimulatory Pathways in CD4 ...

[D.ap]

Mechanisms of CTLA4-Mediated Negative Costimulation

CTLA4 expression and function is intrinsically linked with T-cell activation. CTLA4 is immediately upregulated following T-cell receptor (TCR) engagement (signal 1), with its expression peaking 2 to 3 days after activation (8, 9). CTLA4 dampens TCR signaling through competition with the costimulatory molecule CD28 for the B7 ligands B7-1 (CD80) and B7-2 (CD86), for which CTLA4 has higher avidity and affinity (refs. 10–12; Fig. 1). Because both B7-1 and B7-2 provide positive costimulatory signals through CD28 (refs. 13; signal 2), competitive inhibition of both molecules by CTLA4 is necessary to effectively attenuate T-cell activation. CD28 and CTLA4 also display rapid binding kinetics with B7-1 (12), which, coupled with differences in binding strengths, allows for swift competitive inhibition by CTLA4. In addition to upregulation of CTLA4 expression upon T-cell activation, CTLA4 contained in intracellular vesicles is rapidly trafficked to the immunologic synapse (14). The degree of CTLA4 recruitment to the immunologic synapse correlates directly with TCR signal strength. Once trafficked to the immunologic synapse, CTLA4 is stabilized by B7 ligand binding, allowing it to accumulate and effectively outcompete CD28 (15). Through this mechanism, CTLA4 attenuates positive costimulation by CD28 and thus limits CD28 downstream signaling, which is primarily mediated by PI3K and AKT (16, 17). This results in robust regulation of TCR signal amplitude and, thus, T-cell activity. Because CTLA4-negative costimulation is intrinsically linked to expression of B7 ligands and CD28-mediated positive costimulation, CTLA4 primarily functions to regulate T-cell activity at sites of T-cell priming (e.g., secondary lymphoid organs). In addition to this core function, CTLA4 also attenuates T-cell activation in peripheral tissues given that B7 ligands are constitutively expressed to varying degrees by antigen-presenting cells (APC) but can also be expressed by activated T cells. Because of its central role in regulating T-cell activation, negative costimulation by CTLA4 is critical for tolerance. Reflective of this, biallelic genetic deletion of Ctla4 leads to massive lymphoproliferation that mice succumb to at 3 to 4 weeks of age (18–20).