TGF-β: the apex predator of immune checkpoints.

Future OncologyAhead of Print CommentaryOpen AccessTGF-β: the apex predator of immune checkpointsBryan Oronsky, Pedro Cabrales, Babak Alizadeh, Scott Caroen, Meaghan Stirn, Jeannie Williams & Tony R ReidBryan Oronsky *Author for correspondence: Tel.: +1 858 947 6635; E-mail Address: boronsky@epicentrx.comhttps://orcid.org/0000-0002-3940-6329Department of Research and Development, EpicentRx, Inc. Torrey Pines, CA 92037, USASearch for more papers by this author, Pedro Cabrales https://orcid.org/0000-0002-8794-2839Department of Bioengineering, University of California at San Diego (UCSD) La Jolla, CA 92093, USASearch for more papers by this author, Babak AlizadehDepartment of Research and Development, EpicentRx, Inc. Torrey Pines, CA 92037, USASearch for more papers by this author, Scott CaroenDepartment of Research and Development, EpicentRx, Inc. Torrey Pines, CA 92037, USASearch for more papers by this author, Meaghan StirnDepartment of Research and Development, EpicentRx, Inc. Torrey Pines, CA 92037, USASearch for more papers by this author, Jeannie WilliamsDepartment of Research and Development, EpicentRx, Inc. Torrey Pines, CA 92037, USASearch for more papers by this author & Tony R ReidDepartment of Research and Development, EpicentRx, Inc. Torrey Pines, CA 92037, USASearch for more papers by this authorPublished Online:28 Jul 2023https://doi.org/10.2217/fon-2023-0491AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: AdAPT-001immunogenic cell death (ICD)RRx-001TGF-βTGF-β is a central cytokine with anti-immune and anti-inflammatory activity which finds itself at the tip or apex of the immune checkpoint ‘food chain’. Immune checkpoints – which include PD-1, PD-L1 or CTLA-4 and several others – collectively blunt immune recognition [1]. On the one hand, tumors are heterogeneous structures, and therefore it is perhaps not entirely precise to designate TGF-β as a top-down cytokine which exercises dominance over other immune checkpoints. On the other hand, tumors are inherently hierarchical [2], like the normal tissues that they grotesquely mimic [3]; hence TGF-β, which widely induces immunological tolerance and contravenes T-cell reactivation from checkpoint inhibitors and other immunotherapies, is presumed to act in the capacity of an apex predator that commands and ‘rules’ from above. TGF-β exercises such generalist, top-down control over so many cancer hallmarks that it shapes the behavior of the immune–tumor ecosystem to an even greater degree than the well-delineated PD-1 and CTLA-4 checkpoints, which must ‘look over their shoulders’ at TGF-β [1].A range of cancer immunotherapies – including cancer vaccines, oncolytic viruses, chimeric antigen receptor T-cell therapies, cytokines and immune checkpoint inhibitors – all share a common obstacle to their success: immunosuppression, which, despite best efforts, is not easily overcome. Therefore a major clinical focus is to boost immune responses and to delay or prevent resistance with immunotherapy combinations.Given that both cancer cells and their supporting stromal cells are known to overexpress TGF-β, the combination of TGF-β inhibitors with cancer immunotherapies has the potential to reprogram the immunosuppressive tumor microenvironment and to make the cancer cells themselves more therapeutically responsive. For example, cancer vaccines, which mainly present concentrated tumor-associated or tumor-specific antigens, have so far failed to meet expectations, possibly in part because of how difficult it is to overcome immunosuppression.Mechanistically, a strategy to enhance the activity of cancer vaccines involves the use of TGF-β antagonists which counteract the immunosuppressive activity of TGF-β [4]. Nevertheless, against expectations, the clinical evaluation of therapeutic cancer vaccines which prevent TGF-β synthesis and activation has shown that they perform inconsistently. Belagenpumatucel-L (Lucanix™) is a TGF-β2 antisense cancer vaccine, and gemogenovatucel-T (Vigil®) is a whole autologous tumor cell vaccine that targets the TGF-β1 and TGF-β2 isoforms [5]. In a phase III maintenance trial for belagenpumatucel-L in non-small-cell lung cancer, no survival benefit was observed over placebo, which led investigators to stop the trial after an interim analysis [6]. However, gemogenovatucel-T has demonstrated potential activity as a maintenance treatment in advanced (stage III + IV) ovarian cancer [7]. Relatedly, several TGF-β pathway-targeting agents in development have so far not been successful in the clinic. The most notable of these is bintrafusp alfa, a TGF-β trap + an anti-PD-L1 bispecific antibody whose development was reportedly halted after a series of failed clinical trials in multiple tumor types [8].One potential explanation for the lack of clear-cut and definitive efficacy with these TGF-β-targeted cancer vaccines and TGF-β inhibitors is that they themselves do not directly induce immunogenic tumor cell death (ICD). The importance of ICD is that it releases highly immunostimulatory damage-associated molecular patterns like calreticulin, which may prime tumor-specific T-cell responses [9,10]. For this reason, these TGF-β-targeted vaccines have the potential to combine well with genuine ICD inducers like chemotherapy, radiotherapy or an oncolytic virus like AdAPT-001. The latter is a tumor-specific replicating oncolytic adenovirus currently in a phase II trial called BETA PRIME (NCT04673942) with or without a checkpoint inhibitor [11–13].AdAPT-001 delivers a TGF-β trap transgene, which sequesters and neutralizes TGF-β1 [14,15]. AdAPT-001 has the potential to attract effector T cells that have been re-educated with a cancer vaccine [16]. Preliminary activity in BETA PRIME has been reported with AdAPT-001 as a single agent; this includes three partial responses in 28 patients, five patients with prolonged stable disease for >6 months, documented abscopal effects in non-injected lesions and secondary peaks of viremia despite the presence of neutralizing adenoviral antibodies [17].Another ICD inducer which also lowers TGF-β levels, in addition to its inhibition of the NLRP3 inflammasome / transcription factor complex NF-κB signaling pathway, is RRx-001. This small molecule is under evaluation in an ongoing phase III trial called REPLATINUM to treat small-cell lung cancer and in a phase IIb first-line head and neck cancer trial called KEVLARx [18–21]. RRx-001 has been granted US FDA fast-track designation as an anti-oral mucositis agent.Hopefully, within 5 years, through their elimination of the TGF-β ‘apex predator’, anti-TGF-β cancer vaccines or single-agent TGF-β inhibitors augmented with ICD inducers will make tumor types that are known to be immunologically ‘cold’ (e.g., pancreatic, ovarian, prostate and colorectal tumors) immunoreactive or ‘hot’ and, therefore, much more likely than they are at present to benefit from treatment.Author contributionsB Oronsky and T Reid drafted, critically reviewed and revised the manuscript. P Cabrales, B Alizadeh, S Caroen, M Stirn and J Williams edited and reviewed the final version and approved the content and the decision to submit.Financial & competing interests disclosureThe authors are employees of EpicentRx, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/References1. Larson C, Oronsky B, Carter CA et al. TGF-beta: a master immune regulator. Expert Opin. Ther. Targets 24(5), 427–438 (2020).Crossref, Medline, CAS, Google Scholar2. Cheng C, Andrews E, Yan KK, Ung M, Wang D, Gerstein M. An approach for determining and measuring network hierarchy applied to comparing the phosphorylome and the regulome. Genome Biol. 16(1), 63 (2015).Crossref, Medline, Google Scholar3. Magee JA, Piskounova E, Morrison SJ. 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REPLATINUM Phase III randomized study: RRx-001 + platinum doublet versus platinum doublet in third-line small cell lung cancer. Future Oncol. 15(30), 3427–3433 (2019).Link, CAS, Google Scholar21. Bonomi M, Blakaj DM, Kabarriti R et al. PREVLAR: Phase 2a randomized trial to assess the safety and efficacy of RRx-001 in the attenuation of oral mucositis in patients receiving head and neck chemoradiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 116(3), 551–558 (2023).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Ahead of Print STAY CONNECTED Metrics History Received 31 May 2023 Accepted 29 June 2023 Published online 28 July 2023 Information© 2023 The AuthorsKeywordsAdAPT-001immunogenic cell death (ICD)RRx-001TGF-βAuthor contributionsB Oronsky and T Reid drafted, critically reviewed and revised the manuscript. P Cabrales, B Alizadeh, S Caroen, M Stirn and J Williams edited and reviewed the final version and approved the content and the decision to submit.Financial & competing interests disclosureThe authors are employees of EpicentRx, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/PDF download