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Use of caloric restriction mimetics for potentiating chemo-immunotherapy for the treatment of cancers

A technology of caloric restriction and chemotherapy, applied in chemical instruments and methods, immunoglobulin, drug combination, etc., can solve problems that have not been studied in combination of chemotherapy and/or immunotherapy and calorie restriction simulants

Pending Publication Date: 2021-01-12
INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM) +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] However, the combination of chemotherapy and / or immunotherapy with caloric restriction mimics has never been studied

Method used

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  • Use of caloric restriction mimetics for potentiating chemo-immunotherapy for the treatment of cancers
  • Use of caloric restriction mimetics for potentiating chemo-immunotherapy for the treatment of cancers
  • Use of caloric restriction mimetics for potentiating chemo-immunotherapy for the treatment of cancers

Examples

Experimental program
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Effect test

Embodiment 1

[0198] Immune checkpoint sensitization by a combination of chemotherapy and starvation. Burdens occur in subcutaneous locations with distinct syngeneic tumors (average 20mm 3 ) immunocompetent mice were first treated with systemic chemotherapy (mitoxantrone, MTX, intraperitoneal injection (i.p), or PBS as vehicle control) alone or in combination with a fasting regimen (48 hours, before chemotherapy) Treatment, followed by randomization, received either immunotherapy (antibodies that block CTLA-4 or PD-1) or isotype control antibodies, as schematically shown in Figure 1A. Tumor growth was monitored continuously. The combination therapy that most frequently produced tumor-free mice at the endpoint of the experiment (defined as 50 days after day 0 of the chemotherapy day) consisted primarily of the combined utilization of starvation, chemotherapy and immunotherapy. No or very few complete responses leading to tumor eradication were seen in any of the other groups (PBS control, ...

Embodiment 2

[0203] CD11b blockade interferes with the anticancer effects of hydroxycitrate-conjugated chemotherapy. The combination of the progesterone analog medroxyprogesterone and repetitive DNA lesions produced by gavage of 2,4-dimethoxybenzaldehyde (DMBA) is effective in inducing breast cancer when administered to young female BALB / c mice Very effective (data not shown). In this model, the combination of mitoxantrone (MTX)-based chemotherapy with CRM hydroxycitrate (HC) was highly effective in reducing tumor growth and prolonging mouse survival (data not shown), far more than either alone MTX and HC are more effective 26 . These results were obtained in a "realistic" setting, where cancers can be diagnosed by palpation and thus reach 25mm 2 of the surface, the treatment begins. Notably, repeated injections of a monoclonal antibody (M1 / 70) that blocked CD11b-dependent extravasation of myeloid cells 15 Significantly interfered with the reduction in tumor growth by HC+MTX (data not...

Embodiment 3

[0211] As detailed below, further in vivo experiments are ongoing.

[0212]In vivo experiments. Tumor implantation was performed by subcutaneous / orthotopic injection of XMCA205 / MC38 / PC3 / TC1 tumor cells (in 100 [mu]l PBS) in the right abdomen / orthotopic location of the mice. Tumor volumes were monitored using digital calipers and calculated according to the following formula: volume = length x width x height / 8 x 4 / 3 pi or by appropriate imaging modality (CT scan, PET scan, fluorescence imaging). When the tumor reaches an average of 20mm 3 , mice were fasted (no food for 48 hours, but had free access to water) or were given a caloric restriction mimic (CRM), such as hydroxycitrate (HC; 5 mg / ml per day, in drinking water), or treated with Treat with mitoxantrone (MTX; 5.17 mg / kg ip in 200 μl PBS), oxaliplatin, carboplatin + pemetrexed, oxaliplatin + 5FU, or paclitaxel / Nab-paclitaxel, or with immunological tests Point Inhibitor (ICI) anti-PD-1 (10 mg / kg ip in 200 μl PBS) and / or...

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Abstract

In most cases, cancer chemotherapy and immunotherapy fail to yield durable responses, and complete and permanent regression of established tumors are rare. Here the inventors show that so-called caloric restriction mimetics (CRMs), which are natural or synthetic compounds that pharmacologically mimic the effects of fasting or caloric restriction, can be used to enhance the probability of cancer cure. The administration of several chemically distinct CRMs (such as hydroxycitrate, lipoic acid and the natural polyamine spermidine) led to the complete regression and the induction of protective anticancer immune responses in mouse models. This effect was achieved when CRMs were combined with chemotherapy and immunotherapy targeting the immune checkpoint molecules CTLA-4 and / or PD-l. Hence, caloric restriction and CRMs can be used to sensitize cancers to chemo-immunotherapy.

Description

[0001] field of invention [0002] The present invention relates to the use of mimetics of caloric restriction for enhancing chemoimmunotherapy in cancer treatment. [0003] Background of the invention [0004] Caloric restriction and fasting constitute effective dietary control to induce autophagy and mediate positive effects on organismal health. Caloric restriction mimics (CRMs) are compounds that mimic the biochemical and physiological consequences of caloric restriction and fasting. CRM stimulates autophagy mainly in the cytoplasm of cells by promoting the deacetylation of cellular proteins. This deacetylation process can be achieved by three classes of compounds: (i) compounds that deplete the cytoplasmic pool of acetyl-CoA (AcCoA; the sole donor of acetyl groups); (ii) inhibit acetyltransferases (which make a series of A group of enzymes that acetylate lysine residues in proteins) or (iii) compounds that stimulate the activity of deacetylases thereby reversing the acti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/132A61K31/137A61K31/19A61K31/4155A61K31/616A61P35/00A61K39/395
CPCA61K31/132A61K31/137A61K31/19A61K31/4155A61K31/616A61K39/395A61K45/06A61P35/00A61K31/194A61K31/385A61K31/136A61K2039/505A61K2300/00C07K16/2818
Inventor G·克洛伊梅S·莱维斯克乔纳森·波尔
Owner INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)
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