Julianne Dunphy, PhD, Global Director, Medical Strategy at Mind+Matter, part of EmerGENE, shares a series of standout findings presented at the 63rd American Society of Hematology (ASH) annual meeting and exposition in December 2021.
In today’s blog, Julianne explores the topic of patient gut microbiota and the implications this has on CAR-T treatment efficacy.
Patient gut microbiota may affect CAR-T cell treatment outcomes
Intriguing findings from a pair of studies, one clinical and one preclinical, have provided compelling evidence that a patient’s gut microbiome may have an impact on CAR-T treatment outcomes.
While the intestinal microbiota has been known to affect checkpoint-based immunotherapeutic treatment outcomes among others, the study by Melody Smith, MD et al. explored how the effect might extend to CD19-targeted CAR-T treatment in the clinical setting[i]. PIM antibiotics (piperacillin-tazobactam, imipenem-cilastatin, and meropenem) are known to modulate the gut microbiome. Interestingly, the study found that a group of ALL and NHL patients who had taken PIM antibiotics prior to treatment experienced worse outcomes, including inferior overall survival compared to patients that did not receive antibiotics. They also looked at the baseline microbial milieu in fecal samples from patients receiving CAR-T therapy compared to healthy controls. They found significantly lower microbial diversity in the CAR-T treatment-receiving group, a signal of gut microbiome perturbation already existing in these patients.
On the other hand, a preclinical study looking at the impact of the antibiotic vancomycin on CAR-T treatment outcomes showed an improvement in tumor responses in mice with cancer that had received the antibiotic treatment[ii]. Interestingly, this was true whether the mice had prior healthy donor fecal transplants or not, suggesting the result was unlikely unrelated to health of the baseline gut microbiome.
The questions this raises
These results show the importance of the bacterial milieu of the gut in CD19 CAR-T cell treatment efficacy (and safety, not discussed here) outcomes. This further highlights the important relationship between the gut microbiome and the immune systems. The data also underscore the complexity of these effects and raise numerous questions. Are there specific bacteria or classes therein associated with good outcomes or is it the sheer diversity that matters? What is the mechanism of the effect? And perhaps most importantly for the future, how can we utilize these findings in proactively managing the intestinal microbiome in patients receiving treatment? As is usually the case in hematology and oncology, further study and robust clinical trials are needed. Definitely a topic to watch.
Find out more
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[i] Melody Smith, et al. 253 The Intestinal Microbiota Correlates with Response and Toxicity after CAR T Cell Therapy in Patients with B-Cell Malignancies. Abstract available at: https://ash.confex.com/ash/2021/webprogram/Paper153945.html
[ii] Marco Ruella, et al. 163 Gut Microbiota Tuning Promotes Tumor-Associated Antigen Cross Presentation and Enhances CAR T Antitumor Effects. Abstract available at: https://ash.confex.com/ash/2021/webprogram/Paper151093.html