`
`III III 0 III DID IID III IDI 100 III DID IIDI II DI II
`
`USO 107657 10B2
`
`(12) United States Patent
`Zitvogel et al.
`
`(10) Patent No.: US 10,765,710 B2
`(45) Date of Patent:
`Sep. 8, 2020
`
`(54) COMBINATION OF ONCOLYTIC VIRUS
`WITH IMMUNE CHECKPOINT
`MODULATORS
`
`(71) Applicants: Institut Gustave-Roussy, Villejuif
`(FR); Transgene SA, Illkirch
`Graffenstaden (FR)
`
`(72)
`
`Inventors: Laurence Zitvogel, Paris (FR); Xavier
`Preville, Saint Louis (FR); Laetitia
`Fend, Le Kremlin-bicetre (FR)
`
`(73) Assignees: Institut Gustave-Roussy, Villejuif
`(FR); Transgene SA, Illkirch
`Graffenstaden (FR)
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.:
`
`15/325,576
`
`(22) PCT Filed:
`
`Jul. 16, 2015
`
`(86) PCT No.:
`§ 371 (c)(1),
`(2) Date:
`
`PCT/EP2O1S/066353
`
`Jan. 11, 2017
`
`(87) PCT Pub. No.: W02016/009017
`
`PCT Pub. Date: Jan. 21, 2016
`
`(65)
`
`Prior Publication Data
`
`US 2017/0143780 Al May 25, 2017
`
`(30)
`
`Foreign Application Priority Data
`
`USPC ............................................424/133.1, 178.1
`See application file for complete search history.
`
`(56)
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`References Cited
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`U.S. PATENT DOCUMENTS
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`4/2008
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`WO 97/20574
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`Jul. 16, 2014
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`(EP) ..................................... 14306155
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`OTHER PUBLICATIONS
`
`(2015.01)
`(2015.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A61K 35/768
`A61K35/28
`C07K 16/20
`C07K 16/30
`C12N 5/00
`A61K 9/00
`A61K 38/19
`A61K 39/395
`C07K 16/28
`C12N 7/00
`A6JK 39/00
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`CPC ..........A61K 35/768 (2013.01); A61K 9/0019
`(2013.01); A61K 35/28 (2013.01); A61K
`38/193 (2013.01); A61K39/3955 (2013.01);
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`
`(58) Field of Classification Search
`CPC
`A61K 35/768; A61K 35/28; A61K 9/0019
`
`Rojas et a! (Clin Cancer Res. Dec. 15, 2015; 21(24): 5543555l).*
`(Continued)
`
`Primary Examiner Lynn A Bristol
`
`(74) Attorney, Agent, or Firm
`Belisario & Nadel LLP
`
`Panitch Schwarze
`
`(57)
`
`ABSTRACT
`
`The present invention provides a combination comprising at
`least an oncolytic virus and one or more immune checkpoint
`modulator(s) for use for the treatment of a proliferative
`disease such as cancer. It also relates to a kit comprising an
`oncolytic virus and one or more immune checkpoint modu-
`lator(s) in separate containers. It also concerns a pharma-
`ceutical composition comprising effective amount of an
`oncolytic virus and one or more immune checkpoint modu-
`lator(s).
`
`14 Claims, 6 Drawing Sheets
`
`TRANSGENE/BIOINVENT
`EXHIBIT 1004
`
`Page 1 of 28
`
`

`

`US 10,765,710 B2
`Page 2
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`WO WO 2010/0 14784
`WO WO 2012/110360
`WO WO 2013/043569
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`mental) Journal of Clinical Oncology (May 20, 2012).
`Part Al: Information Required Under Article 11 (Schedule 2) of the
`2002 Regulations, BN Immunotherapeutics, Inc. (Sep. 13, 2012).
`Rizvi et al., Safety and clinical activity of MK-3475 as initial
`therapy in patients with advanced non-small cell lunch cancer
`(NSCLC), 30(15 Supplemental) Journal of Clinical Oncology (May
`20, 2012).
`Seiwert et al., A phase lb study ofMK-3475 in patients with human
`papillomavirus (HPV)-associated and non-HP V-associated head
`and neck (H/N) cancer, 30(15 Supplemental) Journal of Clinical
`Oncology (May 20, 2012).
`Verbrugge et al., Radiotherapy Increases the Permissiveness of
`Established Mammary Tumors to Rejection by Immunomodulatory
`Antibodies, 72(13) Cancer Res 3163-3 174 (Jul. 1, 2012).
`Westin et al., Safety and Activity of PDi Blockade by Pidilizumab
`in Combination with Rituximab in Patients with Relapsed Follicular
`Lymphoma: a Single Group, Open-label, Phase 2 Trial, 15(1)
`Lancet Oncol. 69-77 (Jan. 2014).
`
`* cited by examiner
`
`Page 4 of 28
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`

`

`U.S. Patent
`
`Sep. 8, 2020
`
`Sheet 1 of 6
`
`US 10,765,710 B2
`
`Figure 1A
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`Page 5 of 28
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`

`

`U.S. Patent
`
`Sep. 8, 2020
`
`Sheet 2 of 6
`
`US 10,765,710 B2
`
`Figure 1C
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`
`Page 6 of 28
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`

`

`U.S. Patent
`
`Sep. 8, 2020
`
`Sheet 3 of 6
`
`US 10,765,710 B2
`
`Figure 3A
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`Page 7 of 28
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`

`

`U.S. Patent
`
`Sep. 8, 2020
`
`Sheet 4 of 6
`
`US 10,765,710 B2
`
`Figure 4
`
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`Page 8 of 28
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`

`

`U.S. Patent
`
`Sep. 8, 2020
`
`Sheet 5 of 6
`
`US 10,765,710 B2
`
`•11
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`Page 9 of 28
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`

`U.S. Patent
`
`Sep. 8, 2020
`
`Sheet 6 of 6
`
`US 10,765,710 B2
`
`Figure 6
`
`Combination with anti-PD1 (250 pg/mice)
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`
`12
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`15
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`Page 10 of 28
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`

`US 10,765,710 B2
`
`1
`COMBINATION OF ONCOLYTIC VIRUS
`WITH IMMUNE CHECKPOINT
`MODULATORS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a U.S. National Stage Application
`pursuant to 35 U.S.C. § 371 of International Patent Appli-
`cation PCT/EP2015/066353, filed on Jul. 16, 2015, and
`published as WO 2016/009017 on Jan. 21, 2016, which
`claims priority to European Patent Application 14306155.4,
`filed on Jul. 16, 2014, all of which are incorporated herein
`by reference in their entireties for all purposes.
`
`FIELD OF THE INVENTION
`
`The present invention generally relates to the field of
`oncolytic virotherapy and more specifically to compositions
`and methods to treat, prevent, or inhibit proliferative dis-
`eases, especially cancer. Embodiments include an oncolytic
`virus for use for the treatment of cancer in combination with
`one or more immune checkpoint modulator(s). Embodi-
`ments also include a kit comprising such components and
`method of treatment using said oncolytic virus with said one
`or more immune checkpoint modulator(s).
`Each year, cancer is diagnosed in more than 12 million
`subjects worldwide. In industrialized countries, approxi-
`mately one person out five will die of cancer. Although a vast
`number of chemotherapeutics exist, they are often ineffec-
`tive, especially against malignant and metastatic tumors that
`establish at a very early stage of the disease. Moreover,
`antitumor immunity is often ineffective due to the fact that
`tumor cells have evolved mechanisms to escape host
`defense. One of the major mechanisms of immune suppres-
`sion is a process known as "T-cell exhaustion", which results
`from chronic exposure to antigens and is characterized by
`the upregulation of inhibitory receptors. These inhibitory
`receptors serve as immune checkpoints in order to prevent
`uncontrolled immune reactions. Various immune check-
`points acting at different levels of T cell immunity have been
`described in the literature, including programmed cell death
`protein 1 (PD-i) and its ligands PD-Li and PD-L2, CTLA-4
`(cytotoxic T-lymphocyte associated protein-4), LAG3
`(Lymphocyte-activation gene 3), B and T lymphocyte
`attenuator, T-cell immunoglobulin, mucin domain-contain-
`ing protein 3 (TIM-3), and V-domain immunoglobulin sup-
`pressor of T cell activation.
`Whatever the mechanism of action, these immune check-
`points can inhibit the development of an efficient anti-tumor
`immune response. There is increasing interest in the possible
`therapeutic benefits of blocking such immune checkpoints as
`a means of inhibiting immune system tolerance to tumors
`and thus rescue exhausted antitumor T cells (Leach et al.,
`1996, Science 271: 1734-6). A vast number of antagonistic
`antibodies have been developed during the last decade (e.g.
`anti Tim3, -PD-Li, -CTLA-4, -PDi, etc) and most impor-
`tantly, some have been associated with objective clinical
`responses in cancer patients. Antibodies targeting CTLA-4
`are already marketed (e.g. Ipilimumab, Yervoy, Bristol-
`Myers Squibb, BMS) for metastatic melanoma. BMS
`reported that from 1800 melanoma patients treated with
`ipilimumab 22% are still alive 3 years later. Antibody
`therapies with anti PD-Li (e.g. MPDL328OA, Roche), anti
`PD-i (e.g. Nivolumab, BMS) are also ongoing.
`Another therapeutic approach that is emerging in the field
`of cancer is oncolytic viruses (Hermiston, 2006, Curr. Opin.
`
`5
`
`15
`
`2
`Mol. Ther. 8: 322-30). Oncolytic viruses are capable of
`selective replication in dividing cells (e.g. cancer cell) while
`leaving non dividing cells (e.g. normal cells) unharmed. As
`the infected dividing cells are destroyed by lysis, they
`release new infectious virus particles to infect the surround-
`ing dividing cells. Cancer cells are ideal hosts for many
`viruses because they have the antiviral interferon pathway
`inactivated or have mutated tumour suppressor genes that
`enable viral replication to proceed unhindered (Chemajo-
`10 vsky et al., 2006, British Med. J. 332: 170-2). A number of
`viruses including adenovirus, reovirus, measles, herpes sim-
`plex, Newcastle disease virus and vacciia have now been
`clinically tested as oncolytic agents.
`Some viruses are naturally oncolytic (such as reovirus and
`the Seneca valley picomavirus) while others are engineered
`for tumor selectivity by modifying the viral genome. Such
`modifications include functional deletions in essential viral
`genes, the use of tumor- or tissue-specific promoters to
`20 control the viral gene expression and tropism modification to
`redirect virus to the cancer cell surface.
`The first oncolytic virus to be approved by a regulatory
`agency was a genetically modified adenovirus named Hi0i
`(Shanghai Sunway Biotech) that gained approval in 2005
`25 from China's State Food and Drug Administration (SFDA)
`for the treatment of head and neck cancer. Another oncolytic
`adenovirus, named ONYX-015 is in ongoing clinical trials
`for the treatment of various solid tumors (in phase III for the
`treatment of recurrent head and neck cancer) (Cohen et al.,
`30 2001, Curr. Opin. Investig. Drugs 2: 1770-5). As another
`example, oncolytic herpes simplex 1 (T-VEC) was geneti-
`cally engineered to attenuate the virus virulence, increase
`selectivity for cancer cells and enhance antitumor immune
`response
`(through GM-CSF
`(Granulocyte-macrophage
`35 colony-stimulating factor) expression). Clinical efficacy in
`unresectable melanoma has been demonstrated in Phase II
`and Phase III clinical trials (Senzer et al, 2009, J. Clin.
`Oncol. 27: 5763-71).
`Vaccinia viruses (VV) possess many of the key attributes
`40 necessary for use in oncolytic virotherapy such as natural
`tropism for tumors, strong lytic ability, short life cycle with
`rapid cell-to-cell spread, highly efficient gene expression
`and a large cloning capacity. In addition, they have been
`delivered to millions of individuals during the smallpox
`45 eradication campaign without major safety concerns. In this
`respect, a TK (Thymidine Kinase) and VGF (for VV growth
`factor) double deleted VV expressing GM-CSF (named
`JX-963) showed significant cancer selectivity in tumor bear-
`ing mice (Thome et al., 2007, J Clin Invest. 117: 3350-8).
`50 On the same line, JX-594, a TK-deleted VV (Wyeth strain)
`armed with GM-CSF, has shown promising clinical data,
`and a randomized Phase III trial in hepatocellular carcinoma
`is expected to start soon.
`Combination therapies have also been described in the
`55 literature. WO20i0/014784 describes the combination of an
`anti CTLA4 antibody with chemotherapeutics used for treat-
`ing cancer such as GLEEVEC, TAXOL and the like.
`WO20i4/047350 envisages a recombinant oncolytic virus
`with a gene encoding an anti-PD-i antibody inserted in the
`60 viral genome.
`
`Technical Problem
`
`One may expect that cancer will continue to be a serious
`65 global health threat for many years due to the high number
`of causal factors that may act together or separately to
`initiate or promote the development of a cancer. Moreover,
`
`Page 11 of 28
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`

`US 10,765,710 B2
`
`3
`malignant and especially metastatic tumors are often resis-
`tant to conventional therapies explaining the significant
`morbidity of some cancers.
`Thus, there is an important need to develop more effective
`approaches, for improving prevention and treatment of such 5
`proliferative
`diseases,
`and
`especially
`combination
`approaches.
`The combination therapy, wherein an oncolytic virus and
`one or more immune checkpoint modulator(s) were both
`administered, provided a synergistic immune response as 10
`compared to either approach used alone. Surprisingly, the
`combined treatment wherein an oncolytic vaccinia virus was
`administered before administration of an anti-checkpoint
`antibody such as anti-PD-i or anti-CTLA-4, improved the
`anti-tumor response as evidenced in an appropriate model 15
`animal, thus potentially providing an effective and powerful
`therapy against cancer. Accordingly, the embodiments pro-
`vided herein provide a significant advance in the treatment
`and prevention of proliferative diseases such as cancer.
`This technical problem is solved by the provision of the 20
`embodiments as defined in the claims.