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Antitumor Efficacy of Combined CTLA4/PD-1 Blockade Without Intestinal

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Antitumor Efficacy of Combined CTLA4/PD-1 Blockade Without Intestinal Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2020-001584 on 30 October 2020. Downloaded from Antitumor efficacy of combined CTLA4/ PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions 1 1 1 2 1 David Bauché , Smita Mauze, Christina Kochel, Jeff Grein, Anandi Sawant, Yulia Zybina,2 Wendy Blumenschein,2 Peng Yang,3 Lakshmanan Annamalai,3 Jennifer H Yearley,3 Juha Punnonen,1 Edward P Bowman,1 Alissa Chackerian,1 Drake Laface1 To cite: Bauché D, Mauze S, ABSTRACT of anti- PD-1 and anti- CTLA4 in metastatic Kochel C, et al. Antitumor Background Programmed cell death protein 1 (PD-1) and melanoma, renal cell carcinoma (with efficacy of combined CTLA4/ CTLA4 combination blockade enhances clinical efficacy platinum- doublet chemotherapy), and PD-1 blockade without intestinal in melanoma compared with targeting either checkpoint inflammation is achieved by non- small cell lung cancer ( www. fda. gov). alone; however, clinical response improvement is coupled elimination of FcγR interactions. The incidence of serious immune- with increased risk of developing immune- related adverse Journal for ImmunoTherapy related adverse events (irAE) associated events (irAE). Delineating the mechanisms of checkpoint of Cancer 2020;8:e001584. with immune checkpoint blockade such doi:10.1136/jitc-2020-001584 blockade-media ted irAE has been hampered by the lack of animal models that replicate these clinical events. as colitis or rash is approximately 20% for nivolumab or pembrolizumab (anti- ► Additional material is Methods We have developed a mouse model of published online only. To view, checkpoint blockade-media ted enterocolitis via prolonged PD-1) treated patients and 28% in ipilim- please visit the journal online administration of an Fc- competent anti- CTLA4 antibody. umab (anti- CTLA4)- treated patients. IrAE (http:// dx. doi. org/ 10. 1136/ jitc- Results Sustained treatment with Fc-effector , but not incidence increased to about 60% when 2020- 001584). Fc-mutant or Fc-null, anti-CTLA4 antagonist for 7 weeks pembrolizumab or nivolumab is combined resulted in enterocolitis. Moreover, combining Fc-null or 4 5 7 AC and DL contributed equally. with ipilimumab. Notably, the safety Fc-mutant CTLA4 antagonists with PD-1 blockade results profile improves by reducing the dose in potent antitumor combination efficacy indicating that of ipilimumab used in combination with Accepted 09 October 2020 Fc-effector function is not required for combination benefit. These data suggest that using CTLA4 nivolumab in metastatic renal cell carci- http://jitc.bmj.com/ Conclusion 8 9 antagonists with no Fc-effector function can mitigate gut noma and melanoma. The biological inflammation associated with anti-CTLA4 antibody therapy mechanisms driving irAE in this setting are yet retain potent antitumor activity in combination with not fully known, but a common hypothesis PD-1 blockade. is a combination of increased T- cell effector function driven by dual immune check- point blockade and depletion of regula- on September 27, 2021 by guest. Protected copyright. INTRODUCTION tory T- cells (Tregs) driven by anti- CTLA4 Immunotherapy has taken a prominent antibody- dependent cytotoxicity (ADCC) 10 11 role in the treatment of a number of cancer mechanisms are key contributors. It © Author(s) (or their indications.1 2 Recent clinical successes has been difficult to study the mechanisms employer(s)) 2020. Re- use permitted under CC BY. using antibody blockade of immune check- involved in checkpoint blockade- mediated Published by BMJ. point inhibitory receptors expressed on irAE due to a lack of preclinical models 1Discovery Oncology, Merck & T cells such as CTLA4 or PD- (L)1 have that mirror these clinical adverse effects. Co. Inc, South San Francisco, transformed the treatment options for Preclinical studies in mouse tumor California, USA models have supported the molecular 2 some patients with cancer. As monothera- Molecular Discovery, Merck & design of PD-1 and CTLA4 antibodies that Co. Inc, South San Francisco, pies, these antibodies have demonstrated California, USA enhanced antitumor responses and benefi- are approved for clinical use. Specifically, 3Anatomic Pathology, Merck & cial clinical outcomes in controlled random- binding activating FcγRs and eliciting Co. Inc, South San Francisco, ized clinical trials.3 4 Additional efficacy is FcγR- mediated effector functions such as California, USA achieved with combination approaches.4–6 ADCC is not desired for the anti- PD-1 anti- Correspondence to Multiple combinations are currently being body class to avoid depletion of the bene- Dr David Bauché; investigated in patients and several have ficial antitumor CD8+ effector T- cells that david. bauche@ merck. com been approved, including the combination express PD-1. Antitumor responses driven Bauché D, et al. J Immunother Cancer 2020;8:e001584. doi:10.1136/jitc-2020-001584 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-001584 on 30 October 2020. Downloaded from by surrogate anti- mouse PD-1 antibodies require no antagonists with different abilities to interact with Fc effector function and surrogate antimouse PD-1 FcγRs henceforth referred to Fc- effector (antibody antibodies that do engage activating FcγRs (ie, mouse clone 9D9 on a mouse IgG2a isotype with full ability to IgG2a isotype) have no antitumor activity.12 Accord- bind activating FcγRs), Fc- mutant (antibody clone 9D9 ingly, the anti- PD-1 antibodies used in clinical practice on a mouse IgG1 backbone with a D265A mutation use the human IgG4 isotype with reduced activating that eliminates binding to FcγRs), and Fc- null (Fc- less FcγR effector function.13 bivalent anti- CTLA4 VHH coupled to an albumin- In contrast, mouse studies indicate that activating binding VHH for half- life extension). Anti- CTLA4 FcγR binding is required to achieve monotherapy treatments exacerbate existing colitis in mouse models antitumor efficacy with surrogate anti- mouse CTLA4 that employ irritants which induce intestinal epithelial antibodies.14 15 Mouse antitumor immune responses damage such as dextran sodium sulfate, but no model are particularly sensitive to the presence of Tregs16 17 to date has demonstrated that anti- CTLA4 treatment and anti- CTLA4 antibodies that bind activating FcγR can drive intestinal inflammation de novo.21 22 Dele- (ie, mouse IgG2a isotype) effectively deplete tumor tion of CTLA-4 during adulthood leads to autoim- Tregs which express more CTLA4 on their cell surface mune disease in mice23; therefore, we hypothesized compared with effector T- cells.15 16 It is unclear whether that prolonged CTLA-4 neutralization might mimic tumor Treg depletion occurs in humans following anti- irAE observed in clinic. Treatment of naïve Balb/c CTLA4 antibody dosing and, if so, what contribution mice biweekly with Fc- effector anti- CTLA4 antibody Treg depletion contributes to efficacy.18–20 Ipilimumab, for 7 weeks resulted in weight loss (figure 1A) associ- approved for use in monotherapy and in combination ated with increased intestinal permeability (figure 1B) with anti- PD-1, has the human IgG1 isotype with potent and severe enterocolitis (figure 1C–E). Histological binding to activating FcγRs. inflammation progresses from the small intestine to We examined the contribution of the Fc portion the colon and was associated with immune cell infil- of surrogate anti- mouse CTLA4 antibodies in driving tration in the lamina propria and mucus release into both antitumor efficacy as well as gut inflammation the lumen with mild diarrhea. No obvious immune with the hypothesis that the antitumor requirement cell infiltration was observed in kidney, liver, or lung for anti- CTLA4 antibody’s Fc- effector function will be after prolonged treatment with Fc- effector anti- CTLA4 circumvented when combined with PD-1 blockade. A (online supplemental figure 1A). Proinflammatory key impediment for assessing the influence of Fc- ef- genes such as Il1b, Tnfa, Ifng, Stat1, Il22 and Inos were fector function on the induction of gut inflamma- upregulated in the colon from mice treated with Fc- ef- tion in syngeneic tumor models has been the lack of fector anti- CTLA4 as early as 10 days post treatment measurable inflammation and colitis using surrogate (online supplemental figure 1B) before histological anti- mouse CTLA4 antibodies. Thus, we developed a disease was observed (online supplemental figure 1C). novel model of enterocolitis mediated by anti- CTLA4 Combination of Fc- effector anti- CTLA4 antibody with treatment in mice. We show that Fc- effector function anti- PD-1 antibody significantly aggravated intestinal http://jitc.bmj.com/ is required for anti- CTLA4- driven intestinal inflamma- inflammation (figure 1A–E) as mice started to lose tion and the inflammation is further exacerbated on weight 20 days post- treatment initiation. Importantly, combination treatment with anti- PD-1. Furthermore, intestinal inflammation was not observed when mice immune checkpoint blockade- induced intestinal were dosed with the Fc- mutant anti- CTLA4 antibody or inflammation is driven by effector T- cells and macro- Fc- null anti- CTLA4 VHH with anti- PD-1 demonstrating phages but is independent of Treg depletion. Finally, that FcγR function is required for Fc- effector anti- on September 27, 2021 by guest. Protected copyright. CTLA4 antagonists that lack Fc effector function CTLA4- mediated intestinal inflammation (figure 1, (Fc- mutant antibody or
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