Order of administration of combination cytokine therapies can decouple toxicity from efficacy in syngeneic mouse tumor models

Rothschilds, Adrienne M.; Tzeng, Alice; Mehta, Naveen K.; Moynihan, Kelly D.; Irvine, Darrell J.; Wittrup, K. Dane

doi:10.1080/2162402x.2018.1558678

Cited by 10 publications

(11 citation statements)

References 58 publications

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“…In stark contrast, no mice were cured when MSA-IL2 was combined with IFNα, MSA-IFNα, or IFNβ. However, we and others have observed that cytokine combinations can exacerbate treatment-related toxicities (21,54,55). Extended half-life MSA-IFNα combined with MSA-IL2 led to substantial weight loss, and four out of seven mice were killed due to toxicity (Fig.…”

Section: Resultsmentioning

confidence: 88%

Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies

Lutz

Agarwal

Momin

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Effective antitumor immunity in mice requires activation of the type I interferon (IFN) response pathway. IFNα and IFNβ therapies have proven promising in humans, but suffer from limited efficacy and high toxicity. Intratumoral IFN retention ameliorates systemic toxicity, but given the complexity of IFN signaling, it was unclear whether long-term intratumoral retention of type I IFNs would promote or inhibit antitumor responses. To this end, we compared the efficacy of IFNα and IFNβ that exhibit either brief or sustained retention after intratumoral injection in syngeneic mouse tumor models. Significant enhancement in tumor retention, mediated by anchoring these IFNs to coinjected aluminum-hydroxide (alum) particles, greatly improved both their tolerability and efficacy. The improved efficacy of alum-anchored IFNs could be attributed to sustained pleiotropic effects on tumor cells, immune cells, and nonhematopoietic cells. Alum-anchored IFNs achieved high cure rates of B16F10 tumors upon combination with either anti-PD-1 antibody or interleukin-2. Interestingly however, these alternative combination immunotherapies yielded disparate T cell phenotypes and differential resistance to tumor rechallenge, highlighting important distinctions in adaptive memory formation for combinations of type I IFNs with other immunotherapies.

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Section: Resultsmentioning

confidence: 88%

Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies

Lutz

Agarwal

Momin

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Preclinical research suggests that antiangiogenic agents could exert a priming of the immune microenvironment [12-15, 17-19, 30]. Particularly, the sequence in which these agents are administered (sequential versus concurrently with immunotherapy) might be of key importance [25,26]. The efficacy assessment and the correlative studies results deserve attention.…”

Section: Discussionmentioning

confidence: 99%

“…The efforts invested in studying immune-boosting combinations, however, have paid little attention to the timing of administration of the "immune enhancer". The natural rhythms of innate and adaptive response could be used to enhance the efficacy of anti-PD-1/PD-L1 agents by combining them with agents in the right sequence [25,26]. In that sense, it is possible that pre-treatment with a VEGF-A inhibitor could exert an immuno-priming effect that would increase the chance of response to subsequent immune checkpoint blockade and be more effective than concurrent therapy [26], while causing less adverse events [12].…”

Section: Introductionmentioning

confidence: 99%

Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial

et al. 2020

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Background Preclinical research suggests that the efficacy of immune checkpoint inhibitors in breast cancer can be enhanced by combining them with antiangiogenics, particularly in a sequential fashion. We sought to explore the efficacy and biomarkers of combining the anti-PD-L1 durvalumab plus the antiangiogenic bevacizumab after bevacizumab monotherapy for advanced HER2-negative breast cancer. Methods Patients had advanced HER2-negative disease that progressed while receiving single-agent bevacizumab maintenance as a part of a previous chemotherapy plus bevacizumab regimen. Treatment consisted of bi-weekly durvalumab plus bevacizumab (10 mg/kg each i.v.). Peripheral-blood mononuclear cells (PBMCs) were obtained before the first durvalumab dose and every 4 weeks and immunophenotyped by flow-cytometry. A fresh pre-durvalumab tumor biopsy was obtained; gene-expression studies and immunohistochemical staining to assess vascular normalization and characterize the immune infiltrate were conducted. Patients were classified as “non-progressors” if they had clinical benefit (SD/PR/CR) at 4 months. The co-primary endpoints were the changes in the percentage T cell subpopulations in PBMCs in progressors versus non-progressors, and PFS/OS time. Results Twenty-six patients were accrued. Median PFS and OS were 3.5 and 11 months; a trend for a longer OS was detected for the hormone-positive subset (19.8 versus 7.4 months in triple-negatives; P = 0.11). Clinical benefit rate at 2 and 4 months was 60% and 44%, respectively, without significant differences between hormone-positive and triple-negative (P = 0.73). Non-progressors’ tumors displayed vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors. Non-progressors also showed increased T-effector and T-memory signatures and decreased TREG signatures in gene expression studies in baseline—post-bevacizumab—tumors compared with progressors. Notably, analysis of PBMC populations before durvalumab treatment was concordant with the findings in tumor samples and showed a decreased percentage of circulating TREGs in non-progressors. Conclusions This study reporting on sequential bevacizumab+durvalumab in breast cancer showed encouraging activity in a heavily pre-treated cohort. The correlative studies agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing TREGs cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting. Trial registration (www.clinicaltrials.gov): NCT02802098. Registered on June 16, 2020.

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“…One theory is that multiple redundant immunosuppressive pathways must be targeted in the tumor and that combination approaches could sufficiently disable these layered defenses to illicit a potent antitumor immune response. , Combinatorial immunotherapy is challenging in several ways, with the most notable perhaps being significant increases in toxicity seen in clinical trials . Combining immunomodulating agents is also complicated by schedule-dependent effects that are only beginning to be understood but that have a clear and significant effect on both safety and efficacy. − Initial studies into combination immunotherapy are also revealing that dosing strategies might not need to resemble the conventional approaches established by chemotherapy, such as multiple cycles of drug. For example, clinical trials that combined PD-1 and CTLA-4 checkpoint antibodies reported that patients who ultimately discontinued the trial due to toxicity saw similar benefits to patients who completed the trial. , These data provide a provocative basis to explore different dosing frequencies and strategies.…”

Section: Hydrogels For Drug Deliverymentioning

confidence: 99%

Translational Applications of Hydrogels

et al. 2021

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Advances in hydrogel technology have unlocked unique and valuable capabilities that are being applied to a diverse set of translational applications. Hydrogels perform functions relevant to a range of biomedical purposesthey can deliver drugs or cells, regenerate hard and soft tissues, adhere to wet tissues, prevent bleeding, provide contrast during imaging, protect tissues or organs during radiotherapy, and improve the biocompatibility of medical implants. These capabilities make hydrogels useful for many distinct and pressing diseases and medical conditions and even for less conventional areas such as environmental engineering. In this review, we cover the major capabilities of hydrogels, with a focus on the novel benefits of injectable hydrogels, and how they relate to translational applications in medicine and the environment. We pay close attention to how the development of contemporary hydrogels requires extensive interdisciplinary collaboration to accomplish highly specific and complex biological tasks that range from cancer immunotherapy to tissue engineering to vaccination. We complement our discussion of preclinical and clinical development of hydrogels with mechanical design considerations needed for scaling injectable hydrogel technologies for clinical application. We anticipate that readers will gain a more complete picture of the expansive possibilities for hydrogels to make practical and impactful differences across numerous fields and biomedical applications.

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Order of administration of combination cytokine therapies can decouple toxicity from efficacy in syngeneic mouse tumor models

Cited by 10 publications

References 58 publications

Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies

Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies

Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial

Translational Applications of Hydrogels

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