Checkpoint inhibitor and a whole cell Mycobacterium for use in cancer therapy
Inventors
AKLE, CHARLES • Grange, John • Bilyard, Kevin
Assignees
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Publication Number
US-10925952-B2
Publication Date
2021-02-23
Expiration Date
Abstract
An immunomodulator for use in the treatment, reduction, inhibition or control of a neoplastic disease in a patient intended to undergo checkpoint inhibition therapy, simultaneously, separately or sequentially with administration of the immunomodulator. The immunomodulator preferably comprises a whole cell Mycobacterium, for example, M. vaccae or M. obuense.
Core Innovation
The invention provides a method of treating, reducing, inhibiting or controlling a pancreatic neoplasia in a human patient using multiple intravenous administrations of a therapeutically effective amount of an anti-CTLA-4 antibody and/or an anti-PD-1 antibody. The improvement comprises further administering two or more doses of whole cell, heat-killed Mycobacterium obuense, administered simultaneously, separately or sequentially with respect to the anti-CTLA-4 antibody and/or anti-PD-1 antibody.
The whole cell, heat-killed Mycobacterium obuense is administered in a per-dose amount of 0.1 mg to 1 mg, and both the whole cell, heat-killed Mycobacterium obuense and the anti-CTLA-4 antibody and/or anti-PD-1 antibody are administered on multiple days. The method results in enhanced therapeutic efficacy relative to administration of the anti-CTLA-4 antibody and/or anti-PD-1 antibody alone.
The document further discloses synergistic enhanced therapeutic efficacy of a combination checkpoint inhibitor cancer therapy using an immunomodulator comprising whole cell heat-killed Mycobacterium, including Mycobacterium vaccae or Mycobacterium obuense, with checkpoint blockade such as anti-CTLA-4 and anti-PD-1/PD-L1. It states enhanced therapeutic efficacy versus checkpoint inhibitor or immunomodulator alone and includes broad cancer/neoplasia applicability with pancreatic cancer and metastasis reduction.
In an in vivo xenograft model, the document describes anti-PD-L1 combined with heat-killed Mycobacterium obuense (IMM101/NCTC 13365) yielding greater tumor size reduction and improved tumor control than either agent alone. The document also references immune-related response criteria including irRC, and response categories including irCR and irPR, as part of assessing therapeutic outcomes.
Claims Coverage
Independent claim clm-00001 focuses on treating pancreatic neoplasia in a human patient using multiple intravenous administrations of anti-CTLA-4 and/or anti-PD-1 combined with two or more doses of whole cell, heat-killed Mycobacterium obuense. The claim centers on the specific combination, the dosing and administration schedule, and enhanced therapeutic efficacy relative to antibody alone.
Pancreatic neoplasia treatment with anti-CTLA-4 and/or anti-PD-1 plus heat-killed Mycobacterium obuense
A method of treating, reducing, inhibiting or controlling a pancreatic neoplasia in a human patient by more than one intravenous administration of a therapeutically effective amount of an anti-CTLA-4 antibody and/or anti-PD-1 antibody, wherein further administering to the human patient two or more doses of whole cell, heat-killed Mycobacterium obuense produces enhanced therapeutic efficacy relative to administration of the anti-CTLA-4 antibody and/or anti-PD-1 antibody alone.
Two or more doses of whole cell, heat-killed Mycobacterium obuense at 0.1 mg to 1 mg per dose
The method further administering two or more doses of whole cell, heat-killed Mycobacterium obuense to the human patient, wherein 0.1 mg to 1 mg of the whole cell, heat-killed Mycobacterium obuense is administered per dose.
Simultaneous, separate, or sequential administration on multiple days
The whole cell, heat-killed Mycobacterium obuense is administered simultaneously, separately or sequentially with respect to the anti-CTLA-4 antibody and/or anti-PD-1 antibody, with each of the whole cell, heat-killed Mycobacterium obuense and anti-CTLA-4 antibody and/or anti-PD-1 being administered on multiple days.
The claim coverage centers on a combination regimen for pancreatic neoplasia using multiple intravenous administrations of anti-CTLA-4 and/or anti-PD-1 together with two or more doses of whole cell, heat-killed Mycobacterium obuense at 0.1 mg to 1 mg per dose, administered simultaneously, separately, or sequentially on multiple days, resulting in enhanced therapeutic efficacy relative to antibody alone.
Stated Advantages
Enhanced therapeutic efficacy relative to administration of the anti-CTLA-4 antibody and/or anti-PD-1 antibody alone.
Synergistic enhanced therapeutic efficacy versus checkpoint inhibitor or immunomodulator alone.
Greater tumor size reduction and improved tumor control in an in vivo xenograft model when anti-PD-L1 is combined with heat-killed Mycobacterium obuense.
Metastasis reduction.
Documented Applications
Treating, reducing, inhibiting or controlling pancreatic neoplasia in a human patient.
Cancer therapy combination including pancreatic cancer and metastasis reduction.
In vivo xenograft/mouse example assessing tumor size reduction and tumor control with anti-PD-L1 plus heat-killed Mycobacterium obuense.
Assessment using immune-related response criteria (irRC), including immune-related complete response (irCR) and immune-related partial response (irPR).
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