For those of you who have flipped through a few of my pages, you already know that I've been talking about the cooties in our guts for years with my first post in 2015 and this post - The gut microbiome AGAIN - as it relates to immunotherapy for melanoma, other cancers, antibiotic use, and fecal transplants! - earlier this year. Now there are these...
Fecal microbiota transplant overcomes resistance to
anti-PD-1 therapy in melanoma patients.
Davar, Dzutsev, McCulloch, et al.
Science. Feb 2021.
Anti-programmed cell death protein 1 (PD-1) therapy provides
long-term clinical benefits to patients with advanced melanoma. The composition
of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models
and cancer patients. To investigate whether resistance to anti-PD-1 can be
overcome by changing the gut microbiota, this clinical trial evaluated the
safety and efficacy of responder-derived fecal microbiota transplantation (FMT)
together with anti-PD-1 in patients with PD-1-refractory melanoma. This
combination was well tolerated, provided clinical benefit in 6 of 15 patients,
and induced rapid and durable microbiota perturbation. Responders exhibited
increased abundance of taxa that were previously shown to be associated with
response to anti-PD-1, increased CD8+ T cell activation, and decreased
frequency of interleukin-8-expressing myeloid cells. Responders had distinct
proteomic and metabolomic signatures, and transkingdom network analyses confirmed
that the gut microbiome regulated these changes. Collectively, our findings
show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the
tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1
advanced melanoma.
Fecal microbiota transplant promotes response in
immunotherapy-refractory melanoma patients. Baruch, Youngster, Ben-Betzalel, et al. Science.
Feb 2021.
The gut microbiome has been shown to influence the response
of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical
mouse models and observational patient cohorts. However, modulation of gut
microbiota in cancer patients has not been investigated in clinical trials. In
this study, we performed a phase 1 clinical trial to assess the safety and
feasibility of fecal microbiota transplantation (FMT) and reinduction of
anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic
melanoma. We observed clinical responses in three patients, including two
partial responses and one complete response. Notably, treatment with FMT was
associated with favorable changes in immune cell infiltrates and gene
expression profiles in both the gut lamina propria and the tumor
microenvironment. These early findings have implications for modulating the gut
microbiota in cancer treatment.
As weird as all this sounds - fecal transplantation may be something to talk to your doc about if you are having trouble getting a response to immunotherapy!
Antibiotic use and the subsequent diminished response to immunotherapy has been noted here before - now this ~
Effects of Antibiotic Use on Outcomes in Cancer
Patients Treated Using Immune Checkpoint Inhibitors: A Systematic Review and
Meta-Analysis. Yu, Zheng, Gao,
et al. J Immunother. Feb 2021.
Antibiotic (ATB) use seems to negatively affect the outcomes
of immune checkpoint inhibitors (ICIs). The aim of this review is to clarify
whether ATB use influences the efficacy of ICI treatment in cancer patients.
Databases of MEDLINE, Embase, and Cochrane Library were searched for reports
published in English between January 2007 and December 2019. We included
studies that compared the outcomes of ATB use and no-ATB use in cancer patients
using ICIs. Two reviewers independently selected eligible studies and extracted
the data. Meta-analysis was performed with pooling of unadjusted hazard ratios
(HRs) for overall survival (OS) and progression-free survival (PFS), and with
pooling of odds ratios (ORs) for objective response rate (ORR). Thirty-eight
studies involving 8409 patients were finally included for qualitative or
quantitative analyses. Cancer types included renal cell carcinoma, non-small
cell lung cancer, urothelial carcinoma, melanoma, gastrointestinal cancer, and
others. Meta-analyses revealed that ATB use was associated with poor OS, PFS
and ORR. Subgroup analysis found that these relationships were not influenced
by cancer type or ICI regimens, but were dependent on the timing of ATB use.
Narrative results of multivariable analyses further confirmed the negative effects
of ATB use on OS and PFS. In cancer patients using ICIs, pre-ATB use close to
the start of ICI treatment (within 60 d) was detrimental to outcomes in terms
of OS, PFS, and ORR.
Use of antibiotics is associated with worse clinical outcomes in patients with cancer treated with immune checkpoint inhibitors: A systematic review and meta-analysis. Tsikala-Vafea, Belani, Vieira, et al. Int J Infect Dis. 2021 May.
Objectives: Observational and experimental studies suggest
that the use of antibiotics close to administration of immune checkpoint
inhibitors (ICI) can have a negative effect on tumour response and patient
survival, due to microbiome dysbiosis and the resultant suppression of host
immune response against neoplastic cells.
Methods: A systematic search of PUBMED and EMBASE was
undertaken for studies published between 1 January 2017 and 1 June 2020,
evaluating the association between the use of antibiotics and clinical outcomes
in patients with cancer treated with ICIs. A meta-analysis of the association
between the use of antibiotics and clinical outcomes was also performed.
Results: Forty-eight studies met the inclusion criteria (12,794 patients). Use of antibiotics was associated with shorter overall survival and progression-free survival, decreased response rate and more disease progression. The negative association between the use of antibiotics and progression-free survival was stronger in patients with renal cell carcinoma or melanoma compared with lung cancer.
Conclusions: Recent use of antibiotics in patients with cancer treated with ICIs was associated with worse clinical outcomes. Such patients may benefit from dedicated antimicrobial stewardship programmes.
As I've said before, when really needed, antibiotics can be life saving. However, I would have some tough meaningful talks with my doc about whether I absolutely needed antibiotics were I facing initiation of immunotherapy.
Finally, from all these years of looking at microbiome data as it relates to immunotherapy and melanoma in particular combined with nutrition course work, my best advice is: Eat your veggies. Up your fiber. Boost your own gut cooties by including yogurt, kefir, kimchi, sauerkraut, and other culture rich foods in your diet. Take antibiotics ONLY if absolutely required - especially before or at the start of immunotherapy treatment. Discuss your microbiome with your oncologist - and if they act like you're talking out your patoot - it might be a sign that you need a new one!!!
Take care, melanoma be crazy! - c
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