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000294332 1001_ $$00000-0002-6875-0954$$aPrasad, Rishika$$b0
000294332 245__ $$aAntibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR T-cell therapy.
000294332 260__ $$aWashington, DC$$bAmerican Society of Hematology$$c2025
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000294332 520__ $$aAntibiotic-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapies. In this study, we observed that prior exposure to broad-spectrum ABX with extended anaerobic coverage like piperacillin-tazobactam and meropenem was associated with worsened anti-CD19 CAR-T therapy survival outcomes in large B-cell lymphoma patients (n=422), compared to other ABX classes. In a discovery subset of these patients (n=67), we found that the use of these ABX was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n=58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery n=40, validation n=28). These findings were recapitulated in an immune-competent CAR-T mouse model, where meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-T cells, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T cell efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy.
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000294332 7001_ $$00000-0003-3785-2007$$aRehman, Abdur$$b1
000294332 7001_ $$00000-0002-5832-6578$$aRehman, Lubna$$b2
000294332 7001_ $$aDarbaniyan, Faezeh$$b3
000294332 7001_ $$0P:(DE-He78)979a7f7b1a3e8638bbb9f838555ee44c$$aBlumenberg, Viktoria$$b4
000294332 7001_ $$00009-0000-7853-4465$$aSchubert, Maria-Luisa$$b5
000294332 7001_ $$aMor, Uria$$b6
000294332 7001_ $$0P:(DE-He78)db5f30359487e0d187d7f7f18eb7750f$$aZamir, Eli$$b7
000294332 7001_ $$0P:(DE-He78)d6e2a991c1003a27b302b66a5477e6cd$$aSchmidt, Sabine$$b8
000294332 7001_ $$aHayase, Tomo$$b9
000294332 7001_ $$00000-0003-0050-1705$$aChia-Chi, Chang$$b10
000294332 7001_ $$00009-0005-1698-6657$$aMcDaniel, Lauren Kelley$$b11
000294332 7001_ $$aFlores, Ivonne$$b12
000294332 7001_ $$aStrati, Paolo$$b13
000294332 7001_ $$aNair, Ranjit$$b14
000294332 7001_ $$00000-0002-1153-2294$$aChihara, Dai$$b15
000294332 7001_ $$aFayad, Luis E$$b16
000294332 7001_ $$00000-0001-7302-8299$$aAhmed, Sairah$$b17
000294332 7001_ $$aIyer, Swaminathan P$$b18
000294332 7001_ $$00000-0001-9748-5486$$aWang, Michael L$$b19
000294332 7001_ $$00000-0003-2735-168X$$aJain, Preetesh$$b20
000294332 7001_ $$00000-0001-6071-8610$$aNastoupil, Loretta J$$b21
000294332 7001_ $$00000-0002-1824-2337$$aWestin, Jason R$$b22
000294332 7001_ $$aArora, Reetakshi$$b23
000294332 7001_ $$00009-0002-6081-3866$$aTurner, Joel Gordon$$b24
000294332 7001_ $$aKhawaja, Fareed$$b25
000294332 7001_ $$aWu, Ranran$$b26
000294332 7001_ $$00000-0003-3067-0972$$aDennison, Jennifer B$$b27
000294332 7001_ $$aMenges, Meghan$$b28
000294332 7001_ $$aHidalgo-Vargas, Melanie$$b29
000294332 7001_ $$aReid, Kayla M$$b30
000294332 7001_ $$00000-0002-6270-3065$$aDavila, Marco L$$b31
000294332 7001_ $$aDreger, Peter$$b32
000294332 7001_ $$aKorell, Felix$$b33
000294332 7001_ $$aSchmitt, Anita$$b34
000294332 7001_ $$aTanner, Mark R$$b35
000294332 7001_ $$00000-0002-4314-5037$$aChamplin, Richard E$$b36
000294332 7001_ $$aFlowers, Christopher R$$b37
000294332 7001_ $$aShpall, Elizabeth J$$b38
000294332 7001_ $$aHanash, Samir$$b39
000294332 7001_ $$00000-0003-1045-4914$$aNeelapu, Sattva S$$b40
000294332 7001_ $$aSchmitt, Michael$$b41
000294332 7001_ $$00000-0003-3905-0251$$aSubklewe, Marion$$b42
000294332 7001_ $$00000-0001-5088-0198$$aFahrmann, Johannes$$b43
000294332 7001_ $$aStein-Thoeringer, Christoph$$b44
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000294332 7001_ $$00000-0002-4824-8844$$aHayase, Eiko$$b47
000294332 7001_ $$aJenq, Robert R$$b48
000294332 7001_ $$aSaini, Neeraj Y$$b49
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