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Ipilimumab administration for advanced melanoma in patients with pre-existing Hepatitis B or C infection: a multicenter, retrospective case series.

Ravi S, Spencer K, Ruisi M, Ibrahim N, Luke JJ, Thompson JA, Shirai K, Lawson D, Bartell H, Kudchadkar R, Gunter NT, Mehnert JM, Lipson EJ - J Immunother Cancer (2014)

Bottom Line: Ipilimumab is associated with potentially serious immune-related adverse events, including autoimmune hepatitis.Although this is a small series, the rate of hepatotoxicity appears similar to what has been seen in the general population treated with ipilimumab, and the ability to administer ipilimumab did not appear to be affected by concomitant hepatitis B or C infection.The use of ipilimumab in patients with metastatic melanoma who have pre-existing hepatitis can be considered among other therapeutic options.

View Article: PubMed Central - PubMed

Affiliation: The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, 1550 Orleans St., Rm. 507, Baltimore, MD 21287 USA.

ABSTRACT
Ipilimumab is a fully human, monoclonal antibody directed against Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) that has demonstrated a survival benefit and durable disease control in patients with advanced melanoma. Ipilimumab is associated with potentially serious immune-related adverse events, including autoimmune hepatitis. Because clinical trials of ipilimumab excluded patients with pre-existing hepatitis B or C infection, there is a paucity of data on the safety of ipilimumab administration to that patient population. Here, we report the largest case series to date of patients with hepatitis B or C who received ipilimumab for advanced melanoma. Two of the nine patients described in this case series experienced fluctuations in their liver function tests (LFTs) and were subsequently treated with corticosteroids. Although this is a small series, the rate of hepatotoxicity appears similar to what has been seen in the general population treated with ipilimumab, and the ability to administer ipilimumab did not appear to be affected by concomitant hepatitis B or C infection. The use of ipilimumab in patients with metastatic melanoma who have pre-existing hepatitis can be considered among other therapeutic options.

No MeSH data available.


Related in: MedlinePlus

The process of T cell exhaustion in chronic viral infection and possible effects of ipilimumab. a) After the introduction of initial antigen (infection), naive CD8+ T cells are primed by antigen and, with concomitant stimulation and ongoing inflammation, mature into effector CD8+ T cells. As the antigen (infection) clears, a subset of the effector CD8+ T cells further differentiate into memory CD8+ T cells with the ability to produce cytokines such as IL-2, tumor necrosis factor (TNF) and interferon-γ (IFN-γ), then degranulate, proliferate and self-rejuvenate. In the event of chronic antigen exposure (infection) and subsequent increasing viral load and persistence of antigen (infection), mature effector CD8+ T cells proceed through a hierarchical process of exhaustion, loss of effector functions including the ability to produce cytokines and degranulate, the progressive expression of inhibitory receptors, and the loss of the ability to proliferate and self-rejuvenate and elimination. These processes culminate in the loss of virus-specific CD8+ T cell responses. b) Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) is an inhibitory receptor expressed on the surface of exhausted CD8+ T cells. It is analogous to, but serves the opposite function of, the CD28 T cell receptor also found on the surface of these cells. Activated antigen presenting cells (APC) loaded with antigen express CD80/86, which can either bind CD28 resulting in a stimulatory signal, or bind to CTLA-4 resulting in attenuation of further intracellular signaling and gene expression and ultimately CD8+ T cell response. c) Ipilimumab is a monoclonal antibody that targets the CTLA-4 receptor on CD8+ T cells. It functions by binding the CTLA-4 receptor, thus preventing CD80/86-CTLA-4 binding and the resultant CD8+ T cell attenuation, thereby halting and potentially reversing the process of CD8+ T cell exhaustion.
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Fig1: The process of T cell exhaustion in chronic viral infection and possible effects of ipilimumab. a) After the introduction of initial antigen (infection), naive CD8+ T cells are primed by antigen and, with concomitant stimulation and ongoing inflammation, mature into effector CD8+ T cells. As the antigen (infection) clears, a subset of the effector CD8+ T cells further differentiate into memory CD8+ T cells with the ability to produce cytokines such as IL-2, tumor necrosis factor (TNF) and interferon-γ (IFN-γ), then degranulate, proliferate and self-rejuvenate. In the event of chronic antigen exposure (infection) and subsequent increasing viral load and persistence of antigen (infection), mature effector CD8+ T cells proceed through a hierarchical process of exhaustion, loss of effector functions including the ability to produce cytokines and degranulate, the progressive expression of inhibitory receptors, and the loss of the ability to proliferate and self-rejuvenate and elimination. These processes culminate in the loss of virus-specific CD8+ T cell responses. b) Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) is an inhibitory receptor expressed on the surface of exhausted CD8+ T cells. It is analogous to, but serves the opposite function of, the CD28 T cell receptor also found on the surface of these cells. Activated antigen presenting cells (APC) loaded with antigen express CD80/86, which can either bind CD28 resulting in a stimulatory signal, or bind to CTLA-4 resulting in attenuation of further intracellular signaling and gene expression and ultimately CD8+ T cell response. c) Ipilimumab is a monoclonal antibody that targets the CTLA-4 receptor on CD8+ T cells. It functions by binding the CTLA-4 receptor, thus preventing CD80/86-CTLA-4 binding and the resultant CD8+ T cell attenuation, thereby halting and potentially reversing the process of CD8+ T cell exhaustion.

Mentions: Chemotherapy-induced reactivation of hepatitis B or C that results in significant hepatic decompensation is well described [4,5]. Higher serum viral load prior to the initiation of therapy may influence risk of reactivation, and high pretreatment HBV DNA levels have been shown to correlate with poor tolerance to cytotoxic chemotherapy [10,11]. Several of these issues are being investigated in ongoing clinical trials. (NCT01658878)A theoretical risk of viral reactivation exists with the use of ipilimumab because of the presence of CTLA-4 on T regulatory (Treg) cells. This sub-population of immunoregulatory T cells suppresses the activation and effector function of CD4+ and CD8+ T cells [12–14]; thus, activating Tregs by blocking CTLA-4 may further impair the ability of T cells to keep viral hepatitis suppressed [15]. On the other hand, HCV viral replication is associated with “exhausted” CD8+ T cells, which express immune-inhibitory receptors, such as CTLA-4 and Programmed Death-1 (PD-1) (see Figure 1; [16]). Blockade of one or more of these immune checkpoints has demonstrated a decrease in HCV viral load and a reversal of HCV-specific T cell exhaustion which may stimulate an antiviral response [6,17–19]. Indeed, this phenomenon may underlie the decrease in viral load observed after administration of ipilimumab in case #3, described above. A similar mechanism may have led to the activation and proliferation of tumor-specific T cells, culminating in a durable anti-tumor response.Figure 1


Ipilimumab administration for advanced melanoma in patients with pre-existing Hepatitis B or C infection: a multicenter, retrospective case series.

Ravi S, Spencer K, Ruisi M, Ibrahim N, Luke JJ, Thompson JA, Shirai K, Lawson D, Bartell H, Kudchadkar R, Gunter NT, Mehnert JM, Lipson EJ - J Immunother Cancer (2014)

The process of T cell exhaustion in chronic viral infection and possible effects of ipilimumab. a) After the introduction of initial antigen (infection), naive CD8+ T cells are primed by antigen and, with concomitant stimulation and ongoing inflammation, mature into effector CD8+ T cells. As the antigen (infection) clears, a subset of the effector CD8+ T cells further differentiate into memory CD8+ T cells with the ability to produce cytokines such as IL-2, tumor necrosis factor (TNF) and interferon-γ (IFN-γ), then degranulate, proliferate and self-rejuvenate. In the event of chronic antigen exposure (infection) and subsequent increasing viral load and persistence of antigen (infection), mature effector CD8+ T cells proceed through a hierarchical process of exhaustion, loss of effector functions including the ability to produce cytokines and degranulate, the progressive expression of inhibitory receptors, and the loss of the ability to proliferate and self-rejuvenate and elimination. These processes culminate in the loss of virus-specific CD8+ T cell responses. b) Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) is an inhibitory receptor expressed on the surface of exhausted CD8+ T cells. It is analogous to, but serves the opposite function of, the CD28 T cell receptor also found on the surface of these cells. Activated antigen presenting cells (APC) loaded with antigen express CD80/86, which can either bind CD28 resulting in a stimulatory signal, or bind to CTLA-4 resulting in attenuation of further intracellular signaling and gene expression and ultimately CD8+ T cell response. c) Ipilimumab is a monoclonal antibody that targets the CTLA-4 receptor on CD8+ T cells. It functions by binding the CTLA-4 receptor, thus preventing CD80/86-CTLA-4 binding and the resultant CD8+ T cell attenuation, thereby halting and potentially reversing the process of CD8+ T cell exhaustion.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4195895&req=5

Fig1: The process of T cell exhaustion in chronic viral infection and possible effects of ipilimumab. a) After the introduction of initial antigen (infection), naive CD8+ T cells are primed by antigen and, with concomitant stimulation and ongoing inflammation, mature into effector CD8+ T cells. As the antigen (infection) clears, a subset of the effector CD8+ T cells further differentiate into memory CD8+ T cells with the ability to produce cytokines such as IL-2, tumor necrosis factor (TNF) and interferon-γ (IFN-γ), then degranulate, proliferate and self-rejuvenate. In the event of chronic antigen exposure (infection) and subsequent increasing viral load and persistence of antigen (infection), mature effector CD8+ T cells proceed through a hierarchical process of exhaustion, loss of effector functions including the ability to produce cytokines and degranulate, the progressive expression of inhibitory receptors, and the loss of the ability to proliferate and self-rejuvenate and elimination. These processes culminate in the loss of virus-specific CD8+ T cell responses. b) Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) is an inhibitory receptor expressed on the surface of exhausted CD8+ T cells. It is analogous to, but serves the opposite function of, the CD28 T cell receptor also found on the surface of these cells. Activated antigen presenting cells (APC) loaded with antigen express CD80/86, which can either bind CD28 resulting in a stimulatory signal, or bind to CTLA-4 resulting in attenuation of further intracellular signaling and gene expression and ultimately CD8+ T cell response. c) Ipilimumab is a monoclonal antibody that targets the CTLA-4 receptor on CD8+ T cells. It functions by binding the CTLA-4 receptor, thus preventing CD80/86-CTLA-4 binding and the resultant CD8+ T cell attenuation, thereby halting and potentially reversing the process of CD8+ T cell exhaustion.
Mentions: Chemotherapy-induced reactivation of hepatitis B or C that results in significant hepatic decompensation is well described [4,5]. Higher serum viral load prior to the initiation of therapy may influence risk of reactivation, and high pretreatment HBV DNA levels have been shown to correlate with poor tolerance to cytotoxic chemotherapy [10,11]. Several of these issues are being investigated in ongoing clinical trials. (NCT01658878)A theoretical risk of viral reactivation exists with the use of ipilimumab because of the presence of CTLA-4 on T regulatory (Treg) cells. This sub-population of immunoregulatory T cells suppresses the activation and effector function of CD4+ and CD8+ T cells [12–14]; thus, activating Tregs by blocking CTLA-4 may further impair the ability of T cells to keep viral hepatitis suppressed [15]. On the other hand, HCV viral replication is associated with “exhausted” CD8+ T cells, which express immune-inhibitory receptors, such as CTLA-4 and Programmed Death-1 (PD-1) (see Figure 1; [16]). Blockade of one or more of these immune checkpoints has demonstrated a decrease in HCV viral load and a reversal of HCV-specific T cell exhaustion which may stimulate an antiviral response [6,17–19]. Indeed, this phenomenon may underlie the decrease in viral load observed after administration of ipilimumab in case #3, described above. A similar mechanism may have led to the activation and proliferation of tumor-specific T cells, culminating in a durable anti-tumor response.Figure 1

Bottom Line: Ipilimumab is associated with potentially serious immune-related adverse events, including autoimmune hepatitis.Although this is a small series, the rate of hepatotoxicity appears similar to what has been seen in the general population treated with ipilimumab, and the ability to administer ipilimumab did not appear to be affected by concomitant hepatitis B or C infection.The use of ipilimumab in patients with metastatic melanoma who have pre-existing hepatitis can be considered among other therapeutic options.

View Article: PubMed Central - PubMed

Affiliation: The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, 1550 Orleans St., Rm. 507, Baltimore, MD 21287 USA.

ABSTRACT
Ipilimumab is a fully human, monoclonal antibody directed against Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) that has demonstrated a survival benefit and durable disease control in patients with advanced melanoma. Ipilimumab is associated with potentially serious immune-related adverse events, including autoimmune hepatitis. Because clinical trials of ipilimumab excluded patients with pre-existing hepatitis B or C infection, there is a paucity of data on the safety of ipilimumab administration to that patient population. Here, we report the largest case series to date of patients with hepatitis B or C who received ipilimumab for advanced melanoma. Two of the nine patients described in this case series experienced fluctuations in their liver function tests (LFTs) and were subsequently treated with corticosteroids. Although this is a small series, the rate of hepatotoxicity appears similar to what has been seen in the general population treated with ipilimumab, and the ability to administer ipilimumab did not appear to be affected by concomitant hepatitis B or C infection. The use of ipilimumab in patients with metastatic melanoma who have pre-existing hepatitis can be considered among other therapeutic options.

No MeSH data available.


Related in: MedlinePlus