. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun. 2019 Jan 28;10(1):465. PubMed.


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  1. We read with great interest the very extensive publication from Dr. Schwartz’ group, which significantly expands on their previous work on checkpoint blockade for treating neurodegenerative diseases. Using both anti-PD-1 and now anti-PD-L1 antibodies, they demonstrate in a large series of animal studies prevention and reversion of cognitive deficits in the well-characterized 5xFAD amyloid transgenic model, and significant protection against cerebral pathology, together with the new finding of increased anti-inflammatory IL10 cytokine. Very interestingly, they extend these findings to tau transgenic animals and further analyze the possible underlying mechanisms.

    We have previously tried to generalize the checkpoint blockade concept to other amyloid transgenic mouse models, with different genetic backgrounds, and in three different animal facilities in pharmaceutical companies. While the checkpoint blockade was confirmed in the periphery in one case, collectively we could not observe a significant impact on brain amyloid pathology in any model (Latta-Mahieu et al., 2018). Experimental conditions cannot be identical (discussed in detail in Latta-Mahieu et al.), and according to Rosenzweig et al. it is indeed of outmost importance to “optimize treatments with the tested antibody in each animal model at each facility.”

    We note that in the two publications from Dr. Schwartz, xenogenic rat anti-PD1 or anti PD-L1 and human anti-PD-L1 antibodies are used and most recently at significant doses, 0.5 and 1.5 mg per mouse. Those, together with the concomitant checkpoint blockade, could participate in enhancing peripheral immune responses and the mobilization of innate immunity in brain. It would be important that such potential “sensitizing/potentiating” factors be elucidated in the future.

    We welcome and congratulate Dr. Schwartz’s group on this new publication and are looking forward to more teams in the world generalizing the checkpoint blockade concept for treating neurodegenerative diseases.


    . Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models. Glia. 2018 Mar;66(3):492-504. Epub 2017 Nov 14 PubMed.

    View all comments by Andreas Ebneth
  2. With regard to Latta-Mahieu et al., 2018, I am confident that the three groups that published this paper would have been able to repeat the positive effect of anti-PD-1 antibody on plaque burden, if they had calibrated the antibody and the treatment protocol in the mouse model that they used, and taken into account the different stages of the disease. The manuscript describes three single experiments, employing animal models that are different from those used in either of our papers. Below, I elaborate on the factors that could explain the failure to detect a decrease in plaque burden, the only read-out that was used to monitor the treatment effect.

    The target of the treatment with anti-PD-1 or anti-PD-L1 is not directed against β-amyloid plaques, but rather, this therapy evokes an immunological pathway that starts in the immune system and facilitates, in synergy with inflammatory cues coming from the brain, the recruitment of immune cells to the brain, together leading to multiple effects that ultimately result in cognitive improvement and neuroprotection. Accordingly, the beneficial effect of the treatment on disease modification is an outcome of the modulation of many processes that contribute to disease escalation; these include, but are not limited to, the clearance of amyloid plaques. In contrast to a treatment that is specifically directed against amyloid pathology, with the primary goal of reducing plaques, and which may or may not affect cognitive performance, in the case of immune checkpoint blockade, the beneficial effect is an outcome of several events that are affected by the therapy, the primary one being immune modulation.  

    Our first paper (Baruch et al., 2016) introduced the concept of adopting immune checkpoint blockade for treating AD, by reporting results of a single dose of anti-PD-1 antibody in 5xFAD mice. In order to generalize the phenomenon, further experiments were needed, including those addressing the mechanism, optimization of the dose/regimen, and testing in additional mouse models, which are all presented in our most recent publication (Rosenzweig et al., 2019). 

    We found that the effect of the antibody is dependent on the dose, and its affinity. Moreover, we found that elevation of IFN-γ, indicating peripheral engagement, is an essential response to the treatment, but is not sufficient. Thus, dosages that were sufficient to induce a peripheral response were insufficient to evoke a central one. In line with that observation, we found that the peripheral immune response can be evoked in wild-type animals as well, though there is no effect on monocyte infiltration and immune activity in their brains, suggesting that IFN-γ is important, but is not a valid marker of efficacy on disease progression of this treatment. In addition, in animal models of dementia, which show no plaque burden, treatment using the correct dose and timing resulted in improved cognition and reduced Tau pathology.

    In Latta-Mathieu et al., 2018, results from three different facilities were presented, which summarize three single experiments. Two of the three experiments reported used Fc chimeras (mIgG1) derived from the RPM1-14 anti-PD-1 antibody; importantly, it was shown that the chimeric Fc region significantly affects the pharmacokinetic profile of such antibodies (Ober et al., 2001), and obviously requires adjustment of the therapeutic dose/regimen. The only experiment which used the same antibody that our team used (Baruch et al., 2016) was carried out by Janssen using the commercially available rat IgG2a anti-PD-1 from BioXcell (clone RMP1-14; Catalog number, BE0146), but was tested on the ThyAPP/PS1 mouse model.

    In light of the above, we suspect that the lack of amyloid-β plaque clearance in all the experiments described in Latta-Mahieu et al., 2018, indicates that the authors, using a single dose, were working under sub-optimal experimental conditions. Based on our understanding of the mechanism, we are currently establishing the nature of the immunological marker of the response induced by the antibody that most closely correlates with treatment efficacy in Alzheimer’s disease modification; such a marker could be used to predict a response leading to disease modification. Until these markers are disseminated, and since the antibodies are not directed at amyloid plaque, the primary dose calibration in any mouse model or facility should be based on disease modification as measured by cognitive performance.


    . Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models. Glia. 2018 Mar;66(3):492-504. Epub 2017 Nov 14 PubMed.

    . PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med. 2016 Feb;22(2):135-7. Epub 2016 Jan 18 PubMed.

    . PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun. 2019 Jan 28;10(1):465. PubMed.

    . Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies. Int Immunol. 2001 Dec;13(12):1551-9. PubMed.

    View all comments by Michal Schwartz
  3. This paper is interesting and extends the group's previous findings. The authors show PD-1 or PD-L1 blockade improved murine AD and tauopathy models. Interestingly, they found that macrophages expressing scavenger receptors are involved in this process. However, the relationship between the PD-1/PD-L1 system, which works in T cells, and macrophage/microglial scavenger receptors has not been well-elucidated. To extend this effect observed in mice to the clinic, it is necessary to clarify the detailed mechanism of how PD-1/PD-L1 blockade reduces plaque burden. It must be cautioned that this treatment may promote neuroinflammation, like multiple sclerosis.

    View all comments by Akihiko Yoshimura
  4. Harnessing the peripheral immune system as a neuroprotective therapeutic approach to Alzheimer's disease: Discussion regarding pathways and mechanism

    Immunotherapy targeting the programmed death protein (PD)-1/PD-L1 pathway was shown to be effective in reducing disease manifestations as measured by cognitive performance and pathology in mouse models of AD and tauopathy (Baruch et al., 2016; Rosenzweig et al., 2019). The results, much as they were novel and provocative, were also met with skepticism, and evoked controversy when another group attempted to replicate these results and failed to show reduction in amyloid plaque deposition, as a single readout (Latta-Mahieu et al., 2018). Nevertheless, recently published papers from additional groups support the role of the peripheral immune system in containing AD (He et al., 2020; Yang et al., 2020), and further demonstrate that treatment directed at the peripheral immune system activates a process of repair, leading to disease modification and cognitive improvement in additional mouse models. These and other studies, cited below, are used here as a platform to explain the failure to reduce amyloid plaque burden as a single readout (Latta-Mahieu et al., 2018). 

    In the recent study by He and colleagues, systemic injection of IFN-γ in APP/PSN1 mice resulted in recruitment of monocyte-derived macrophages, enhanced cognitive performance, and reduction of disease pathology (He et al., 2020). Yang and colleagues showed that, in the APP/PSN1 mouse model, elevation of systemic immunosuppressive mechanisms (regulatory T cells) exacerbates disease progression, which could be overcome by influenza vaccination (Yang et al., 2020). Elevated immune suppression, as well as the negative effect of systemic regulatory T cells shown in this study (Yang et al., 2020), were previously documented in 5xFAD mice as well (Baruch et al., 2015). The effects of systemic IFN-γ injection on the brains of AD mice (He et al., 2020) are also consistent with the effect of short-term depletion of regulatory T-cells (Baruch et al., 2015) or of blocking the PD-1/PD-L1 pathway (Baruch et al., 2016; Rosenzweig et al., 2019), shown to be mediated through IFN-γ-producing T cells (Baruch et al., 2016). In AD, the IFN-γ-producing T cells facilitate recruitment of monocyte-derived macrophages to the diseased brain (Baruch et al., 2016; Rosenzweig et al., 2019). 

    Yang’s results are also consistent with the observed effect of immunization with Bacillus Calmette-Guérin (BCG) in APP/PS1 mice, which reduced the levels of regulatory cells, resulting in a 10-fold increase in the serum levels of IL-2, and a fivefold increase in IFN-γ (Zuo et al., 2017). Also in line with these observations, bladder cancer patients treated with BCG were significantly less likely to develop AD at any age compared with patients who were not treated with this modality (Gofrit et al., 2019). 

    In PD-1 or PD-L1 blockade (Baruch et al., 2016Rosenzweig et al., 2019), similarly to the new studies, described above (He et al., 2020; Yang et al., 2020), the effect of activation of the immune system was shown to be mediated, at least in part, through monocyte-derived macrophages. Monocyte-derived macrophages were repeatedly shown in mouse models of AD and dementia to be beneficial in coping with the disease, by reducing pathological manifestations and enhancing cognitive performance (Baruch et al., 2015; El Khoury et al., 2007; Naert and Rivest, 2011; Simard et al., 2006; Butovsky et al., 2007; Butovsky  et al., 2006; Koronyo et al., 2015; Koronyo-Hamaoui et al., 2009; Schwartz and Shechter, 2010; Greenhalgh et al., 2018; Dionisio-Santos et al., 2019; Li et al., 2020). Notably, such monocyte-derived macrophages, which were often referred to as “monocyte-derived microglia” (Simard et al., 2006; Mildner et al., 2007) or “dendritic-like cells” (Butovsky  et al., 2006), display activities distinct from those of the activated resident microglia (Yamasaki et al., 2014; Thériault  et al., 2015; Ajami et al., 2018). Thus, for example, the beneficial effect observed following blocking of PD-L1/PD-1 pathway was shown to be dependent upon enhanced recruitment to the brain of monocyte-derived macrophages expressing the scavenger receptor, MSR1 (Baruch et al., 2016; Rosenzweig et al., 2019). Myeloid cells expressing MSR1 were shown to be able to remove soluble Aβ (Frenkel et al., 2013), which includes the oligomers, the neurotoxic form of misfolded proteins (Shankar et al., 2007). Removal of these forms was shown to have a direct impact on cognitive performance and synaptic activity (Li et al., 2020), arguing in favor of boosting recruitment of immune cells to the brain (Baruch et al., 2016; Rosenzweig et al., 2019). 

    Recent studies using Trem2-/-5xFAD mice clearly show that cognitive impairment is correlated with the level of soluble Aβ, rather than with levels of insoluble amyloid deposits and plaques, and that Trem2-expressing cells mostly affect plaque pathology, but not soluble oligomers nor cognition, in mice over 6 months of age (Griciuc et al., 2019). 

    Taken, together, the reported apparent failure of anti PD-L1 treatment to show an effect on plaque burden, as a single, acute readout (Latta-Mahieu et al., 2018), can be explained based on the mechanism described above. According to our results, we propose that the effect of anti-PD-L1 or anti-PD-L1 treatment is mediated via monocyte-derived macrophages, which contribute to disease modification by removal of soluble Aβ that contain the neurotoxic oligomers, with effect on plaques or insoluble Aβ representing a secondary outcome, as reduction of Aβ oligomers should result in a fewer or smaller plaques over time.

    Accordingly, measuring plaque burden as a single readout for a treatment that is not directed at plaques is an unreliable marker of treatment effects (Latta-Mahieu et al., 2018). In all other studies in which the immune system was harnessed to treat AD, multiple parameters were measured, as summarized above. In contrast to the measurement of plaques, reduction of soluble toxic oligomers measured by biochemical assays, as well as improvement in cognitive performance, could be expected to be observed following a treatment that targets the PD-1/PD-L1 pathway (Baruch et al., 2016; Rosenzweig et al., 2019) or any similar treatment (He et al., 2020; Yang et al., 2020). Moreover, measuring plaques as a sole readout following PD-1 blockade (Latta-Mahieu et al., 2018) or of any treatment that does not directly target amyloid plaques, provides a limited measure of the efficacy, while soluble Aβ is a valid measure of disease modification, with likely relevance to the clinic.

    To date, treatment with anti-PD-L1 antibody has been repeated in five different mouse models of AD and tauopathy, demonstrating improvement of cognitive performance, reduction via monocyte-derived macrophages of the soluble forms of misfolded proteins, measured biochemically in the brain and in the CSF, and skewing the brain toward an anti-inflammatory state, with an increase in the presence of FoxP3+ regulatory T cells (unpublished data; manuscripts in preparation).

    Based on the data emerging from the novel concept of targeting the PD-1/PD-L1 pathway as an immune-therapy for AD and dementia, a biopharmaceutical company, ImmunoBrain Checkpoint, Inc. (IBC), was founded in 2015. IBC has engineered a proprietary anti-PD-L1 antibody, tailored to the specific therapy mechanism of activity in AD (which is distinct from that in cancer), with a high efficacy and superior safety profile in terms of risk of triggering an adverse autoimmune response (unpublished data). The antibody is currently in production scale-up in order to be ready for first in human clinical trial in 2021. Beyond testing of safety, markers have been established to determine antibody activity mechanism of action in the patient’s blood and CSF.


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    View all comments by Michal Schwartz

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