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Improved mouse models to assess tumour immunity and irAEs after combination cancer immunotherapies.

Liu J, Blake SJ, Smyth MJ, Teng MW - Clin Transl Immunology (2014)

Bottom Line: The current excitement surrounding cancer immunotherapy stems particularly from clinical data involving agents mediating immune checkpoint receptor blockade, which have induced unprecedented efficacy against a range of tumours compared with previous immunotherapeutic approaches.However, an important consideration in targeting checkpoint receptors has been the emergence of associated toxicities termed immune-related adverse events (irAEs).However, one may predict the frequency and severity of irAEs will increase with combinations, which may result in premature therapy cessation, thus limiting the realization of such an approach.

View Article: PubMed Central - PubMed

Affiliation: Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute , Herston, Queensland, Australia ; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute , Herston, Queensland, Australia ; School of Medicine, University of Queensland , Herston, Queensland, Australia.

ABSTRACT
The current excitement surrounding cancer immunotherapy stems particularly from clinical data involving agents mediating immune checkpoint receptor blockade, which have induced unprecedented efficacy against a range of tumours compared with previous immunotherapeutic approaches. However, an important consideration in targeting checkpoint receptors has been the emergence of associated toxicities termed immune-related adverse events (irAEs). In light of the clinical benefits observed after co-blockade of checkpoint receptors and data from preclinical mouse models, there is now a strong rationale to combine different checkpoint receptors together, with other immunotherapies or more conventional therapies to assess if clinical benefits to cancer patients can be further improved. However, one may predict the frequency and severity of irAEs will increase with combinations, which may result in premature therapy cessation, thus limiting the realization of such an approach. In addition, there is a limit to how many different combination therapies that can be tested in a timely manner given the legal, regulatory and budgetary issues associated with conducting clinical trials. Thus, there is a need to develop preclinical mouse models that more accurately inform us as to which immunotherapies might combine best to provide the optimal therapeutic index (maximal anti-tumour efficacy and low level irAEs) in different cancer settings. In this review we will discuss the irAEs observed in patients after checkpoint blockade and discuss which mouse models of cancer can be appropriate to assess the development of tumour immunity and irAEs following combination cancer immunotherapies.

No MeSH data available.


Related in: MedlinePlus

Spectrum of irAEs associated with immunomodulatory antibodies. Although immunomodulatory antibodies such as those that target checkpoint receptors can release endogenous anti-tumour responses, irAEs can be induced through therapy-associated release of cytokines and infiltration of immune effector cells. In cancer patients, treatment with immunomodulatory antibodies particularly with single checkpoint blockade is frequently associated with the development of irAEs. The types of irAEs (proportion and severity) as well and more unique and serious side effects reported in clinical trials with immunomodulatory antibodies such as anti-CTLA-4 (Ipilimumab,18, 49, 61 Tremelimumab62, 63, 64), anti-PD-1 (Nivolumab,19 MK-3475),65 anti-PD-L1 (BMS-936559,66 MPDL3280A67), anti-CD40 (CP-870,893)27, 68 and anti-CD137 (BMS-663513)30 are summarized.
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fig1: Spectrum of irAEs associated with immunomodulatory antibodies. Although immunomodulatory antibodies such as those that target checkpoint receptors can release endogenous anti-tumour responses, irAEs can be induced through therapy-associated release of cytokines and infiltration of immune effector cells. In cancer patients, treatment with immunomodulatory antibodies particularly with single checkpoint blockade is frequently associated with the development of irAEs. The types of irAEs (proportion and severity) as well and more unique and serious side effects reported in clinical trials with immunomodulatory antibodies such as anti-CTLA-4 (Ipilimumab,18, 49, 61 Tremelimumab62, 63, 64), anti-PD-1 (Nivolumab,19 MK-3475),65 anti-PD-L1 (BMS-936559,66 MPDL3280A67), anti-CD40 (CP-870,893)27, 68 and anti-CD137 (BMS-663513)30 are summarized.

Mentions: The induction of irAEs is an important factor to consider when attenuating co-stimulatory and co-inhibitory immune receptors for cancer immunotherapy.3 Thought also has to be given as to how targeting of these receptors in combination or with other therapeutics may induce combination-specific irAEs that may not be predicted or observed by monotherapies. IrAEs are thought to be related to therapy-associated cytokine release and T-cell-mediated organ infiltration17 and different from bona fide autoimmunity as they normally resolve following therapy or with corticosteroids or anti-TNF therapy. IrAEs can generally involve the gastrointestinal, liver, skin, nervous and endocrine systems (Figure 1). In a pooled analysis of 325 patients treated with 10 mg kg−1 of anti-CTLA-4, irAEs of any grade were observed in ∼72.3%.20 Similar proportions were also observed in patients treated with anti-PD-1 alone, although with less severity.19 In most cases, irAEs are mostly mild and generally manageable with appropriate treatment algorithms now having been developed.20 This includes dose interruption/discontinuation and the use of systemic high-dose corticosteroids.21 Specifically, grade 3 or 4 irAEs, which developed in each of these patients (14% for anti-PD-1 and 25% for anti-CTLA-4) warranted attention, as in extreme cases these can be severe and life threatening. Patients who resolve their grade 2 irAEs can recommence treatment, although any grade 3 or 4 irAEs (with the exception of grade 3 skin toxicity) is a contraindication to further therapy with ipilimumab. Importantly, almost all patients (93%) developed irAEs following concurrent anti-PD-1 and anti-CTLA-4 monoclonal antibody therapy with an increase in grade 3 or 4 irAEs (50%) being observed compared with those treated with monotherapy alone.2


Improved mouse models to assess tumour immunity and irAEs after combination cancer immunotherapies.

Liu J, Blake SJ, Smyth MJ, Teng MW - Clin Transl Immunology (2014)

Spectrum of irAEs associated with immunomodulatory antibodies. Although immunomodulatory antibodies such as those that target checkpoint receptors can release endogenous anti-tumour responses, irAEs can be induced through therapy-associated release of cytokines and infiltration of immune effector cells. In cancer patients, treatment with immunomodulatory antibodies particularly with single checkpoint blockade is frequently associated with the development of irAEs. The types of irAEs (proportion and severity) as well and more unique and serious side effects reported in clinical trials with immunomodulatory antibodies such as anti-CTLA-4 (Ipilimumab,18, 49, 61 Tremelimumab62, 63, 64), anti-PD-1 (Nivolumab,19 MK-3475),65 anti-PD-L1 (BMS-936559,66 MPDL3280A67), anti-CD40 (CP-870,893)27, 68 and anti-CD137 (BMS-663513)30 are summarized.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232074&req=5

fig1: Spectrum of irAEs associated with immunomodulatory antibodies. Although immunomodulatory antibodies such as those that target checkpoint receptors can release endogenous anti-tumour responses, irAEs can be induced through therapy-associated release of cytokines and infiltration of immune effector cells. In cancer patients, treatment with immunomodulatory antibodies particularly with single checkpoint blockade is frequently associated with the development of irAEs. The types of irAEs (proportion and severity) as well and more unique and serious side effects reported in clinical trials with immunomodulatory antibodies such as anti-CTLA-4 (Ipilimumab,18, 49, 61 Tremelimumab62, 63, 64), anti-PD-1 (Nivolumab,19 MK-3475),65 anti-PD-L1 (BMS-936559,66 MPDL3280A67), anti-CD40 (CP-870,893)27, 68 and anti-CD137 (BMS-663513)30 are summarized.
Mentions: The induction of irAEs is an important factor to consider when attenuating co-stimulatory and co-inhibitory immune receptors for cancer immunotherapy.3 Thought also has to be given as to how targeting of these receptors in combination or with other therapeutics may induce combination-specific irAEs that may not be predicted or observed by monotherapies. IrAEs are thought to be related to therapy-associated cytokine release and T-cell-mediated organ infiltration17 and different from bona fide autoimmunity as they normally resolve following therapy or with corticosteroids or anti-TNF therapy. IrAEs can generally involve the gastrointestinal, liver, skin, nervous and endocrine systems (Figure 1). In a pooled analysis of 325 patients treated with 10 mg kg−1 of anti-CTLA-4, irAEs of any grade were observed in ∼72.3%.20 Similar proportions were also observed in patients treated with anti-PD-1 alone, although with less severity.19 In most cases, irAEs are mostly mild and generally manageable with appropriate treatment algorithms now having been developed.20 This includes dose interruption/discontinuation and the use of systemic high-dose corticosteroids.21 Specifically, grade 3 or 4 irAEs, which developed in each of these patients (14% for anti-PD-1 and 25% for anti-CTLA-4) warranted attention, as in extreme cases these can be severe and life threatening. Patients who resolve their grade 2 irAEs can recommence treatment, although any grade 3 or 4 irAEs (with the exception of grade 3 skin toxicity) is a contraindication to further therapy with ipilimumab. Importantly, almost all patients (93%) developed irAEs following concurrent anti-PD-1 and anti-CTLA-4 monoclonal antibody therapy with an increase in grade 3 or 4 irAEs (50%) being observed compared with those treated with monotherapy alone.2

Bottom Line: The current excitement surrounding cancer immunotherapy stems particularly from clinical data involving agents mediating immune checkpoint receptor blockade, which have induced unprecedented efficacy against a range of tumours compared with previous immunotherapeutic approaches.However, an important consideration in targeting checkpoint receptors has been the emergence of associated toxicities termed immune-related adverse events (irAEs).However, one may predict the frequency and severity of irAEs will increase with combinations, which may result in premature therapy cessation, thus limiting the realization of such an approach.

View Article: PubMed Central - PubMed

Affiliation: Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute , Herston, Queensland, Australia ; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute , Herston, Queensland, Australia ; School of Medicine, University of Queensland , Herston, Queensland, Australia.

ABSTRACT
The current excitement surrounding cancer immunotherapy stems particularly from clinical data involving agents mediating immune checkpoint receptor blockade, which have induced unprecedented efficacy against a range of tumours compared with previous immunotherapeutic approaches. However, an important consideration in targeting checkpoint receptors has been the emergence of associated toxicities termed immune-related adverse events (irAEs). In light of the clinical benefits observed after co-blockade of checkpoint receptors and data from preclinical mouse models, there is now a strong rationale to combine different checkpoint receptors together, with other immunotherapies or more conventional therapies to assess if clinical benefits to cancer patients can be further improved. However, one may predict the frequency and severity of irAEs will increase with combinations, which may result in premature therapy cessation, thus limiting the realization of such an approach. In addition, there is a limit to how many different combination therapies that can be tested in a timely manner given the legal, regulatory and budgetary issues associated with conducting clinical trials. Thus, there is a need to develop preclinical mouse models that more accurately inform us as to which immunotherapies might combine best to provide the optimal therapeutic index (maximal anti-tumour efficacy and low level irAEs) in different cancer settings. In this review we will discuss the irAEs observed in patients after checkpoint blockade and discuss which mouse models of cancer can be appropriate to assess the development of tumour immunity and irAEs following combination cancer immunotherapies.

No MeSH data available.


Related in: MedlinePlus