Combination tumor immunotherapy

a tumor immunotherapy and tumor technology, applied in the field of tumor immunotherapy, can solve the problems of insufficient understanding of the immunobiology of cancer, inability to predict which of the many different possible combinations, and rare and limited immune response to immune therapy, so as to facilitate the induction of clinically beneficial anti-tumor immunity, inhibit the immune response to tumors, and enhance the step 2 of the cancer immunity cycle.

Pending Publication Date: 2020-09-10
CHECKMATE PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
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Benefits of technology

[0019]The present invention also is based, at least in part, on the finding that delivery of the CpG ODN into tumors (directly or indirectly) induces the expression of adhesion molecules in the local vasculature in and around the tumor, and promotes the egress of activated T cells (CD4+ and CD8+) from capillaries into the tumor and surrounding region. Some of these T cells will be specific to the unmutated and mutated tumor-associated antigens (TAA). In the absence of checkpoint inhibitors and / or XRT, these T cells may be inhibited by the tumor, but in combination, this creates a much more powerful anti-tumor effect than can be achieved with CpG or the checkpoint inhibitors or XRT on their own.

Problems solved by technology

However, despite occasional successes, durable responses to immune therapy have been rare and limited to just a few tumor types.
The art does not teach designs of TLR9 agonists that have improved anti-tumor effects as a result of inducing lower amounts of IL-10 production.
Nevertheless, this increasing recent understanding of the cycle of tumor immunity has heightened awareness that it may be possible to increase the clinical efficacy of cancer immunotherapy by using combinations of agents that act at different points in this cycle for induction of therapeutic immune responses against tumors, but the art does not provide a deep enough understanding of the immunobiology of cancer to predict which of the many different possible combinations will be preferred.
Systemic administration of anti-CTLA-4 antibodies has led to durable responses in ˜10% of patients with melanoma, and some encouraging early results in other tumor types, but at the cost of a high rate of adverse effects, including death in some patients.
Aside from melanoma, in which pre-existing anti-tumor immunity is relatively common, TIL are relatively uncommon in most other tumor types, indicating that CPI may be of limited benefit in most types of cancer.

Method used

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  • Combination tumor immunotherapy
  • Combination tumor immunotherapy
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Examples

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example 1

[0475]In order to achieve optimal synergy for a combination of a CpG ODN and checkpoint inhibitor (+ / −XRT), the CpG ODN should be designed to induce the maximal level of type I IFN possible, with the lowest level of IL-10 possible. Of the CpG ODN classes described above, the closest to this ideal is the A-class. In order to improve the A-class ODN, they can be understood in terms of two semi-independent components: (i) the 5′ and 3′ termini of the A-class CpG ODN, and (ii) the core palindrome. The purpose of the polyG domains in the 5′ and 3′ termini is to form G tetrads that self-assemble into nanoparticles, positioning the palindromes in a favorable way to activate TLR9, and providing a very strong multimerization of TLR9 in the early endosomes, leading to strong IRF3 / 7 activation (and downstream IFN-α secretion) without triggering a more sustained signal that would lead to B cell activation and strong IL-10 production. The G tetrads formed by the polyG domains may also help to st...

example 2

[0494]In vitro experiments were performed to examine the effects of changes in palindrome sequence, number of 5′ and 3′ G, number of 5′ and 3′ phosphorothioate internucleotide linkages, and substitution of 5-iodo-2′-deoxyuridine within the palindromes on IFN-α secretion by human peripheral blood mononuclear cells (PBMCs).

[0495]PBMCs from a normal human donor were cultured in the presence or absence of the indicated ODN in triplicate and results plotted as mean+ / −standard deviation (SD) in FIGS. 4 and 5, for two different human donors. PBMCs were isolated over histopaque-1077 (Sigma) and plated at 1.25×106 / mL, 220 UL / well in RPMI 1640 (10% FBS, glutamine, Pen / Strep) in a 96-well U-bottom tissue culture plate. ODN were added to a final concentration of 5, 1 or 0.2 μg / mL (FIG. 4) or at a lowest concentration of 0.5 pLg / mL (FIG. 5) and cells were incubated for 48 hours. Cells were then spun down and supernatants transferred to new plates and frozen at −20° C. until use. Supernatants wer...

example 3

[0504]In vitro experiments were performed to examine the effects of changes in palindrome sequence, number of 5′ and 3′ phosphorothioate internucleotide linkages, formulation of a native DNA CpG-A ODN in a virus-like particle (VLP), and substitution of 2-O-methyl sugars within the 3′ end of the CpG-A ODN on potency and peak IFN-α secretion by human PBMC.

[0505]Experimental conditions were generally as in Example 2, except that in this case the indicated ODN were cultured with the PBMC in triplicate at the concentrations of 5 μg / mL (concentration or “conc A” in FIGS. 6 and 7); 1 μg / mL (“conc B” in FIGS. 6 and 7) and 0.5 μg / mL (“conc C”) for all of the ODN except for two samples:

[0506]1. The completely PO ODN G10 (labeled as “CYTO003” in FIGS. 6 and 7) was cultured at ODN concentrations of 50 μg / mL (“conc A” in FIGS. 6 and 7), 10 μg / mL (“conc B”) and 2 μg / mL (“conc C”); and

[0507]2. Samples labeled as “CytQbAb” in FIGS. 6 and 7 contained the G10 ODN packaged within a virus-like particle...

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Abstract

Provided are methods for treating cancer using local administration of certain CpG oligonucleotides (CpG ODN) and systemic administration of a checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, and / or an anti-CLA-4 antibody. In preferred embodiments, the CpG ODN are selected based on their propensity to induce high amounts of interferon alpha (IFN-α) and T-cell activation relative to interleukin-10 (IL-10) and B-cell activation. In certain embodiments, the methods further include pretreatment with radiotherapy, to potentiate the combination immunotherapy.

Description

RELATED APPLICATIONS[0001]This application claims priority from U.S. Provisional Patent Application No. 62 / 098,568, filed Dec. 31, 2014; United States Provisional Patent Application No. 62 / 106,526, filed Jan. 22, 2015; and U.S. Provisional Patent Application No. 62 / 118,165, filed Feb. 19, 2015.BACKGROUND OF THE INVENTION[0002]Many scientists have sought to treat cancer by activating the immune system against the tumor. However, despite occasional successes, durable responses to immune therapy have been rare and limited to just a few tumor types. Current understanding of cancer immunotherapy among those skilled in the art has been summarized in recent review articles, including for example Chen and Mellman, Immunity 2013 39(1): 1-10. The cycle for induction of therapeutic immune responses against tumors may be broken down into seven distinct steps (FIG. 1):[0003]1. Release of cancer cell antigens;[0004]2. Presentation of cancer cell antigens by antigen-presenting cells (APC, usually ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/70C12N15/117A61K39/395C07K16/10C07K16/28A61P35/00A61K45/06A61K31/713
CPCC12N2310/17C07K16/2818C12N15/117A61K45/06A61P35/00A61K2039/505A61K39/39541C12N2320/31C07K16/10A61K39/00A61K31/713A61K31/70A61K31/7125A61K2300/00
Inventor KRIEG, ARTHUR
Owner CHECKMATE PHARM INC
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