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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

Common preclinical mouse models of cancers to assess the anti-tumour efficacy of cancer immunotherapies. The advantages and disadvantages of using transplantable and spontaneous mouse models of cancer are listed.
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fig2: Common preclinical mouse models of cancers to assess the anti-tumour efficacy of cancer immunotherapies. The advantages and disadvantages of using transplantable and spontaneous mouse models of cancer are listed.

Mentions: The demonstration that targeting checkpoint receptors activates endogenous anti-tumour immunity and leads to significant clinical benefit in different cancer types now spurs the question of how their efficacy can be further improved through rationale combination approaches. In advanced melanoma, concurrent anti-CTLA-4 and anti-PD-1 therapy resulted in clinical benefits in 50% of patients, which to date is the best result obtained with cancer immunotherapies. Nevertheless, 50% of patients did not respond, and in some cancer types such as pancreas and prostate, checkpoint blockade does not appear to provide any significant clinical benefits. Thus, early-phase clinical trials are exploring how checkpoint inhibitors combine with other agents, including (1) conventional therapies (radiotherapy, chemotherapy), (2) alternative immunotherapies (vaccines, cytokine, adoptive cellular therapy), (3) targeted therapies (BRAF or vascular endothelial growth factor inhibitors)17 or (4) immunomodulatory antibodies.26 With combination immunotherapies increasingly being tested in clinical trials, irAEs will be an ongoing issue that has to be dealt with (as discussed above) as it may limit their usage. Furthermore, even when both agents have regulatory approval and have distinct mechanisms of action and toxicity profile, unexpected specific irAEs induced by the combination can occur. This was illustrated by a recent clinical trial that reported on the unexpected hepatotoxicity observed with melanoma patients after concurrent treatment with a Braf inhibitor (Vemurafenib) and ipilimumab, resulting in cessation of the trial.34 Given the beauracracy, cost and time associated with conducting clinical trials, utilizing preclinical mouse models that can more accurately model tumour immunity and irAEs may allow more informed assessment of which therapies can be combined to induce optimal therapeutic index (Figures 2 and 3).


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)

Common preclinical mouse models of cancers to assess the anti-tumour efficacy of cancer immunotherapies. The advantages and disadvantages of using transplantable and spontaneous mouse models of cancer are listed.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Common preclinical mouse models of cancers to assess the anti-tumour efficacy of cancer immunotherapies. The advantages and disadvantages of using transplantable and spontaneous mouse models of cancer are listed.
Mentions: The demonstration that targeting checkpoint receptors activates endogenous anti-tumour immunity and leads to significant clinical benefit in different cancer types now spurs the question of how their efficacy can be further improved through rationale combination approaches. In advanced melanoma, concurrent anti-CTLA-4 and anti-PD-1 therapy resulted in clinical benefits in 50% of patients, which to date is the best result obtained with cancer immunotherapies. Nevertheless, 50% of patients did not respond, and in some cancer types such as pancreas and prostate, checkpoint blockade does not appear to provide any significant clinical benefits. Thus, early-phase clinical trials are exploring how checkpoint inhibitors combine with other agents, including (1) conventional therapies (radiotherapy, chemotherapy), (2) alternative immunotherapies (vaccines, cytokine, adoptive cellular therapy), (3) targeted therapies (BRAF or vascular endothelial growth factor inhibitors)17 or (4) immunomodulatory antibodies.26 With combination immunotherapies increasingly being tested in clinical trials, irAEs will be an ongoing issue that has to be dealt with (as discussed above) as it may limit their usage. Furthermore, even when both agents have regulatory approval and have distinct mechanisms of action and toxicity profile, unexpected specific irAEs induced by the combination can occur. This was illustrated by a recent clinical trial that reported on the unexpected hepatotoxicity observed with melanoma patients after concurrent treatment with a Braf inhibitor (Vemurafenib) and ipilimumab, resulting in cessation of the trial.34 Given the beauracracy, cost and time associated with conducting clinical trials, utilizing preclinical mouse models that can more accurately model tumour immunity and irAEs may allow more informed assessment of which therapies can be combined to induce optimal therapeutic index (Figures 2 and 3).

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