Microbiota composition, as a marker of responsiveness to anti-pd1/pd-l1/pd-l2 antibodies and use of microbial modulators for improving the efficacy of an anti-pd1/pd-l1/pd-l2 ab-based treatment

Patent metadata

Field	Value
Publication number	US-2021346438-A1
Application number	US-201716472778-A
Country	US
Kind code	A1
Filing date	Dec 22, 2017
Priority date	Dec 22, 2016
Publication date	Nov 11, 2021
Grant date	—

Abstract

The invention relates to gut microbiota profiles associated with response or resistance to treatments with ICB, in particular with anti-PD1 or anti PD-L1 or anti-PD-L2 antibodies. In particular, the invention pertains to a theranostic method for identifying good responders, to whom an anti-PD1 or anti PD-L1 or anti-PD-L2 can be administered, while a pre-treatment based on FMT and/or immunogenic probiotics is recommended to bad responders exhibiting a dysbiosis. In particular, the present invention pertains to Akkermansia muciniphila as the main commensal species distinguishing responders from progressors and its use alone or with E. hirae for the treatment of antibiotics or gut repertoire insufficieny-associated dysbiosis.

First claim

1 - 36 . (canceled)

37 . A method of treating a cancer in a patient, comprising administering to the patient a composition comprising bacteria selected from the group consisting of Enterococcus hirae, Akkermansia muciniphila, Alistipes shahii , other Alistipes species and mixtures thereof, in combination with an anti-PD1/PD-L1/PD-L2 Ab-based therapy, wherein said composition induces immunostimulation in a cancer patient.

38 . The method of claim 37 , wherein the composition comprises bacteria of at least two species selected from the group consisting of Enterococcus hirae, Akkermansia muciniphila, Alistipes species, Eubacterium species, Ruminococcacae, Clostridiales species, Bacteroidales species, Actinobacteria, Coriobacteriales species and Methanobrevibacter smithii.

39 . The method of claim 37 , wherein the composition comprises bacteria of the species Enterococcus hirae and Akkermansia muciniphila.

40 . The method of claim 37 , wherein said composition further comprises bacteria of the species Burkholderia cepacia and/or Bacteroides fragilis and/or Alistipes indistinctus and/or onderdonkii.

41 . The method of claim 37 , wherein said composition comprises:
Clostridiales bacteria of the species Christensenella minuta ; and/or Erysipelotrichia of the species Dielma fastidiosa or Erysipelatoclostridium ramosum ; and/or Alistipes bacteria of species selected from the group consisting of Alistipes shahii, Alistipes indistinctus, Alistipes onderdonkii and Alistipes finegoldii ; and/or Eubacterium bacteria of the species Eubacterium limosum ; and/or Bacteroidales bacteria of the species Bacteroides salyersiae and/or Barnesiella intestinihominis ; and/or Coriobacteriales bacteria of the species Collinsella intestinalis and/or Collinsella tanakaei ; and/or Firmicutes bacteria of the species Flavonifractor plautii.

42 . The method of claim 37 , wherein said composition comprises:
(i) Enterococcus hirae selected from the group consisting of Enterococcus hirae strain 13144 deposited on Nov. 7, 2013 at the Collection Nationale de Cultures de Microorganismes (CNCM) under the number 1-4815, Enterococcus hirae strain IGR7 deposited on Aug. 31, 2017 at the CNCM under the number 1-5224, Enterococcus hirae strain IGR4 deposited on Nov. 27, 2017 at the CNCM under the number CNCM 1-5260, Enterococcus hirae strain IGR11 deposited on Nov. 27, 2017 at the CNCM under the number CNCM 1-5261 and mixtures thereof; and (ii) Akkermansia muciniphila selected from the group consisting of Akkermansia muciniphila strains p2261 and p3415, both deposited at the Collection de souches de l'Unité des Rickettsies (CSUR) and mixtures thereof; and (iii) Eubacterium limosum.

43 . The method of claim 37 , wherein said composition comprises:
(i) Enterococcus hirae selected from the group consisting of Enterococcus hirae strain 13144 deposited on Nov. 7, 2013 at the Collection Nationale de Cultures de Microorganismes (CNCM) under the number 1-4815, Enterococcus hirae strain IGR7 deposited on Aug. 31, 2017 at the CNCM under the number 1-5224, Enterococcus hirae strain IGR4 deposited on Nov. 27, 2017 at the CNCM under the number CNCM 1-5260, Enterococcus hirae strain IGR11 deposited on Nov. 27, 2017 at the CNCM under the number CNCM 1-5261 and mixtures thereof; and (ii) Barnesiella intestinihominis.

44 . The method of claim 37 , wherein said composition comprises:
(i) Enterococcus hirae selected from the group consisting of Enterococcus hirae strain 13144 deposited on Nov. 7, 2013 at the Collection Nationale de Cultures de Microorganismes (CNCM) under the number 1-4815, Enterococcus hirae strain IGR7 deposited on Aug. 31, 2017 at the CNCM under the number 1-5224, Enterococcus hirae strain IGR4 deposited on Nov. 27, 2017 at the CNCM under the number CNCM 1-5260, Enterococcus hirae strain IGR11 deposited on Nov. 27, 2017 at the CNCM under the number CNCM 1-5261 and mixtures thereof; and (ii) Christensenella minuta.

45 . The method of claim 37 , wherein said composition comprises:
(i) Enterococcus hirae selected from the group consisting of Enterococcus hirae strain 13144 deposited on Nov. 7, 2013 at the Collection Nationale de Cultures de Microorganismes (CNCM) under the number 1-4815, Enterococcus hirae strain IGR7 deposited on Aug. 31, 2017 at the CNCM under the number 1-5224, Enterococcus hirae strain IGR4 deposited on Nov. 27, 2017 at the CNCM under the number CNCM 1-5260, Enterococcus hirae strain IGR11 deposited on Nov. 27, 2017 at the CNCM under the number CNCM 1-5261 and mixtures thereof; and (ii) Actinotignum schaalii.

46 . The method of claim 37 , wherein said patient is treated with anti-PD1 and anti-CTLA4 coblockade or with anti-PD-L2 and anti-CTLA4 coblockade.

47 . A method of preventing a cancer relapse in a patient, comprising administering to the patient a composition as recited in claim 37 .

48 . A method of treating a cancer in a patient, comprising administering to the patient a fecal microbial composition in combination with an anti-PD1/PD-L1/PD-L2 Ab-based therapy, wherein said fecal microbial composition has been enriched with a bacterial composition as recited in claim 37 .

49 . The method of claim 37 , comprising a step of assessing, in a feces sample from said patient, the presence of bacteria from one or several species selected from the group consisting of Akkermansia muciniphila, Enterococcus hirae and Dielma fastidiosa wherein if any one of Akkermansia muciniphila Enterococcus hirae and Dielma fastidiosa is absent from said feces sample, the bacterial of fecal microbial composition is administered to the patient before administration of the anti-PD1/PD-L1/PD-L2 Ab-based therapy and/or anti-CTLA-4 Ab-based therapy.

50 . The method of claim 37 , comprising a step of assessing, in a feces sample from said patient, the presence of Ruminococcus sp. CAG:353 , Ruminococcus bacterium LM158 , Ruminococcus torques 2 and Ruminococcaceae bacterium D16, wherein if none of Ruminococcus sp. CAG:353 , Ruminococcus bacterium LM158 , Ruminococcus torques 2 and Ruminococcaceae bacterium D16 is present in said feces sample, the bacterial of fecal microbial composition is administered to the patient before administration of the anti-PD1/PD-L1/PD-L2 Ab-based therapy and/or anti-CTLA-4 Ab-based therapy.

51 . The method of claim 37 , comprising a step of assessing, in a feces sample from said patient, the presence of Alistipes sp. CAG:435 , Alistipes sp. CAG:514 , Alistipes indistinctus CAG328 and Alistipes sp. CAG/268, wherein if none of Alistipes sp. CAG:435 , Alistipes sp. CAG:514 , Alistipes indistinctus CAG328 and Alistipes sp. CAG/268 is present in said feces sample, the bacterial of fecal microbial composition is administered to the patient before administration of the anti-PD1/PD-L1/PD-L2 Ab-based therapy and/or anti-CTLA-4 Ab-based therapy.

52 . The method of claim 37 , comprising a step of assessing, in a feces sample from said patient, the presence of Bacteroides xylanosolvens CAG945, Bacteroides uniformis CAG159, Bacteroides ovatus CAG1165, Prevotella CAG:255, CAG163 , Ruminococcus bromii CAG611, Roseburia intestinalis CAG291 and Eubacterium CAG:38, CAG 629, wherein if Bacteroides xylanosolvens CAG945, Bacteroides uniformis CAG159, Bacteroides ovatus CAG1165, Prevotella CAG:255, CAG163 , Ruminococcus bromii CAG611, Roseburia intestinalis CAG291 or Eubacterium CAG:38, CAG 629 are present in sai

Assignees

• Roussy Inst Gustave
• Inst Nat Sante Rech Med
• Univ Paris Sud
• Inst Nat De La Rech Agronomique Inra

Inventors

• Zitvogel Laurence
• Routy Bertrand
• Le Chatelier Emmanuelle

Classifications

• C12Q1/689

  for bacteria · CPC title

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• C12Q2600/118

  Prognosis of disease development · CPC title

• A61K35/744 Primary

  Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs · CPC title

• A61K2039/55594

  from bacteria · CPC title