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The Role of Opioids in Cancer Response to Immunotherapy
Giulia Pomati
Sapienza University of Rome: Universita degli Studi di Roma La Sapienza
Corresponding Author
ORCiD: https://orcid.org/0000-0001-6715-5443
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities.
Methods: This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival.
Results: One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn’t (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37-2.09, p<0.0001; median OS, 4 months vs. 35months, HR 1.60, 95 % CI 1.26-2.02, p <0.0001). In addition, PFS and OS were significantly impaired in those patients taking corticosteroids, antibiotics or antifungals, in those patients with an ECOG PS ≥1 and in patients with a high tumor burden. Using the multivariate analyses, opioids and ECOG PS were independent prognostic factors for PFS, whereas only ECOG PS resulted to be an independent prognostic factor for OS, with trend toward significance for opioids as well as tumor burden.
Discussion: Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well.
Conclusions: A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes.
Keywords
Immunotherapy, opioids, opioid receptors, prognostic factor, predictive factor, early progression
Figure 1
Dr. Claudia Friesen
commented on 15 February, 2021
When conducting a clinical study, the author should specified which opioids and concentrations of the opioids are used and the duration of the administration of the opioids should be specified. Opioids bind to different opioid receptors. Opioid receptors belong to the large superfamily of seven transmembrane-spanning G protein-coupled receptors. When commenting on opioids, one should note and also discuss the fact that opioids bind and act on different opioid receptors such as delta, kappa, mu, nociceptin receptor, zeta as well as sigma and ε-opioid receptors. In addition opioids are agonists and/or antagonists to the opioid receptors. Opioids can senisitized or desensitized opioid receptors. For example: Methadone as well as morphine works via the mu opioid receptor as a pain killer. However morphine is known also to act through the sensitization of the delta opioid receptor. Sensitization of the delta opioid receptors can lead to tumor growth. On the other hand, the opioid methadone desensitizes the delta opioid receptor and does therefore not lead to the tumor growth via the delta opioid receptor as described for morphine. In addition, the functional desensitization of opioid receptors such as delta opioid receptors by methadone may explain why methadone is effective in the treatment of morphine dependence. Therefore it is very important to know which opioids were given during immunotherapy treatment. In addition the concentration of the opioids and the duration of treatment is necessary to know. The authors cannot generally say that opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well, without the information about the specification of the opioids: the author should specified which opioids are used in these clinical study, because the information is important for further treatment options of cancer patients.
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CURRENT STATUS: Under Revision
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Posted 08 Feb, 2021
Community comments: 1
Review #2 received
Received 11 Feb, 2021
Editorial decision: Minor revision
On 11 Feb, 2021
Review #1 received
Received 05 Feb, 2021
Reviewer #2 agreed
On 30 Jan, 2021
Editor assigned
On 28 Jan, 2021
Reviewers invited
Invitations sent on 28 Jan, 2021
Reviewer #1 agreed
On 28 Jan, 2021
Editor invited
On 28 Jan, 2021
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On 28 Jan, 2021
First submitted
On 27 Jan, 2021
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Translational Medicine
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This preprint is under consideration at Journal of Translational Medicine. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
The Role of Opioids in Cancer Response to Immunotherapy
Giulia Pomati
Sapienza University of Rome: Universita degli Studi di Roma La Sapienza
Corresponding Author
ORCiD: https://orcid.org/0000-0001-6715-5443
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Revision
Version 1
Posted 08 Feb, 2021
Community comments: 1
Review #2 received
Received 11 Feb, 2021
Editorial decision: Minor revision
On 11 Feb, 2021
Review #1 received
Received 05 Feb, 2021
Reviewer #2 agreed
On 30 Jan, 2021
Editor assigned
On 28 Jan, 2021
Reviewers invited
Invitations sent on 28 Jan, 2021
Reviewer #1 agreed
On 28 Jan, 2021
Editor invited
On 28 Jan, 2021
Submission checks complete
On 28 Jan, 2021
First submitted
On 27 Jan, 2021
Metrics
Comments: 1
PDF Downloads: ...
HTML Views: ...
Subject Areas
Translational Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities.
Methods: This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival.
Results: One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn’t (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37-2.09, p<0.0001; median OS, 4 months vs. 35months, HR 1.60, 95 % CI 1.26-2.02, p <0.0001). In addition, PFS and OS were significantly impaired in those patients taking corticosteroids, antibiotics or antifungals, in those patients with an ECOG PS ≥1 and in patients with a high tumor burden. Using the multivariate analyses, opioids and ECOG PS were independent prognostic factors for PFS, whereas only ECOG PS resulted to be an independent prognostic factor for OS, with trend toward significance for opioids as well as tumor burden.
Discussion: Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well.
Conclusions: A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes.
Figure 1
Dr. Claudia Friesen
commented on 15 February, 2021
When conducting a clinical study, the author should specified which opioids and concentrations of the opioids are used and the duration of the administration of the opioids should be specified. Opioids bind to different opioid receptors. Opioid receptors belong to the large superfamily of seven transmembrane-spanning G protein-coupled receptors. When commenting on opioids, one should note and also discuss the fact that opioids bind and act on different opioid receptors such as delta, kappa, mu, nociceptin receptor, zeta as well as sigma and ε-opioid receptors. In addition opioids are agonists and/or antagonists to the opioid receptors. Opioids can senisitized or desensitized opioid receptors. For example: Methadone as well as morphine works via the mu opioid receptor as a pain killer. However morphine is known also to act through the sensitization of the delta opioid receptor. Sensitization of the delta opioid receptors can lead to tumor growth. On the other hand, the opioid methadone desensitizes the delta opioid receptor and does therefore not lead to the tumor growth via the delta opioid receptor as described for morphine. In addition, the functional desensitization of opioid receptors such as delta opioid receptors by methadone may explain why methadone is effective in the treatment of morphine dependence. Therefore it is very important to know which opioids were given during immunotherapy treatment. In addition the concentration of the opioids and the duration of treatment is necessary to know. The authors cannot generally say that opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well, without the information about the specification of the opioids: the author should specified which opioids are used in these clinical study, because the information is important for further treatment options of cancer patients.