EP3706808A1 - Using targeted radiotherapy (trt) to drive anti-tumor immune response to immunotherapies - Google Patents
Using targeted radiotherapy (trt) to drive anti-tumor immune response to immunotherapiesInfo
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- EP3706808A1 EP3706808A1 EP18819480.7A EP18819480A EP3706808A1 EP 3706808 A1 EP3706808 A1 EP 3706808A1 EP 18819480 A EP18819480 A EP 18819480A EP 3706808 A1 EP3706808 A1 EP 3706808A1
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- Prior art keywords
- antibody
- tumor
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- derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
- A61K51/0408—Phospholipids
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3076—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties
- C07K16/3084—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties against tumour-associated gangliosides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
- A61N2005/1019—Sources therefor
- A61N2005/1021—Radioactive fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1092—Details
- A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
- C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor
Definitions
- This disclosure relates generally to methods of treating cancer.
- the disclosure is directed to methods of treating a cancer comprising one or more malignant solid tumors in a subject by (1) systemically administering to the subject an immunomodulatory dose of a targeted radiotherapy (TRT) agent, such as a radioactive metal chelate compound, a radiohalogenated compound, radiolabeled antibody, or a radiosiotope that is differentially taken up by and retained within solid tumor tissue; and (2) systemically administering to the subject one or more immunostimulatory agents, such as one or more immune checkpoint inhibitors.
- TRT targeted radiotherapy
- in situ vaccination a strategy that seeks to enhance tumor immunogenicity, generate tumor infiltrating lymphocytes (TIL) and drive a systemic anti-tumor immune response directed against "unvaccinated,” disseminated tumors.
- TIL tumor infiltrating lymphocytes
- in situ vaccination a malignant solid tumor is injected with (or treated with) one or more agents that facilitate the release of tumor antigens while simultaneously providing pro-inflammatory signals to reverse the immune-tolerizing microenvironment of the tumor [Pierce et al, Human Vaccines & Immunotherapoeutics 11(8): 1901 -1909, 2015; Marabelle et al, Clin. Cancer Res.
- an immunostimulatory agent such as an immune checkpoint inhibitor
- an immunostimulatory agent is administered to circulate through the entire body (e.g., intravenously), rather than being locally injected into the tumor.
- Such agents can be used to treat tumors in which an anti-tumor immune response is present, but has been "exhausted" or rendered ineffective.
- checkpoint inhibitors In the case of checkpoint inhibitors, the tumor cells express "checkpoint ligands" or other checkpoint molecules that interact with "checkpoint receptors" on the existing anti-tumor immune cells, triggering the inactivation of these cells. By blocking this interaction, systemically-administered checkpoint inhibitors turn on the exhausted, pre-existing immune response in cancer patients, facilitating a more effective attack on the cancer cells by the patient's own immune system.
- Radiation hormesis is a decades-old hypothesis that low doses of ionizing RT can be beneficial by stimulating the activation of natural protective repair mechanisms that are not activated in the absence of ionizing RT [Cameron and Moulder, Med. Phys. 25: 1407, 1998].
- the reserve repair mechanisms are hypothesized to be sufficiently effective when stimulated as to not only cancel the detrimental effects of ionizing RT but also inhibit disease not related to RT exposure.
- the abscopal effect is a phenomenon reported in the 1950's, whereby, xRT treatment of one tumor actually causes shrinkage of another tumor outside the RT treatment area. Although rare, this phenomenon is thought to be dependent on activation of the immune system.
- hormesis and the abscopal effect support the potential interaction and stimulation of the immune system by low dosage (immune stimulatory but non-cytotoxic) RT, which may then be combined with other immunologic approaches, such as systemically-administered immunotherapy.
- This concomitant immune tolerance can be overcome, enabling efficacy of in situ vaccination, when xRT is given to all areas of tumor.
- xRT cannot be effectively used in combination with in situ vaccination methods in the presence of multiple tumors, particularly if the tumors are not few in number, or if the location of one or more of the tumors is not precisely known, or if it is not feasible to deliver xRT to all sites of tumor.
- administering xRT to all tumor sites in patients with metastatic disease would likely result in systemic immune suppression, defeating the central purpose of systemically-administered immunotherapy.
- the analog can be used in positron emission tomography-computed tomography (PET/CT) or single-photon emission computed tomography (SPECT) imaging of solid tumors.
- PET/CT positron emission tomography-computed tomography
- SPECT single-photon emission computed tomography
- the analog can be used to treat the solid tumors.
- Such analogs not only target a wide variety of solid tumor types in vivo, but also undergo prolonged selective retention in tumor cells, thus affording high potential as RT agents. Moreover, tumor uptake is limited to malignant cancer and not premalignant or benign lesions.
- metal isotopes that have better properties for optimized imaging and/or RT than the radioactive iodine isotopes used in the previously disclosed alkylphosphocholine analogs.
- 1-124 suffers from poor positron output (only about 24% of the emissions are positrons), and it suffers further from a confounding gamma emission (600 KeV), which actually interferes with normal 511 KeV PET detection.
- Certain positron emitting metals have better imaging characteristics.
- 1-131 produces other non- therapeutic emissions at other energies, which add undesired radiation dosimetry to neighboring normal tissue, including bone marrow.
- the beta particle range of 1-131 is also quite long, which contributes to off target toxicity.
- Several metallic radiotherapy isotopes offer a cleaner emission profile and shorter pathlength and thus less potential toxicity.
- radioiodinated compounds so they are still selectively taken up and retained in tumor cells.
- the chelated radioactive metal isotope provides improved emissions for imaging and/or radiotherapy applications.
- Such agents are well suited for delivering a sub-cytotoxic but immunomodulatory dose of ionizing RT to all malignant tumors present within a subject, regardless of whether their number and locations are known.
- the disclosure encompasses a method of treating a cancer comprising one or more malignant solid tumors in a subject.
- the method includes the steps of systemically administering to the subject (a) an immunomodulatory dose of a targeted radiotherapy (TRT) agent that is differentially taken up by and retained within the malignant solid tumor tissue; and (b) one or more immunostimulatory agents.
- TRT targeted radiotherapy
- the one or more immunostimulatory agents are immune checkpoint inhibitors capable of targeting one or more checkpoint molecules.
- Non-limiting examples of the one or more immune checkpoint inhibitors include agents that are capable of targeting one or more of the following checkpoint molecules: A2AR (adenosine A2a receptor), BTLA (B and T lymphocyte attenuator), CTLA4 (cytotoxic T lymphocyte-associated protein 4), KIR (killer cell immunoglobulin- like receptor), LAG3 (Lymphocyte Activation Gene 3), PD-1 (programmed death receptor 1), PD-L1 (programmed death ligand 1), CD40 (cluster of differentiation 40), CD27 (cluster of differentiation 27), CD28 (cluster of differentiation 28), CD137 (cluster of differentiation 137), OX40 (CD134; cluster of differentiation 134), OX40L (OX40 ligand; cluster of differentiation 252), GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein), GITRL (glucocorticoid-induced tumor necrosis factor receptor-related protein ligand), ICOS (inducible
- the one or more immune checkpoint inhibitors include one or more anti-immune checkpoint molecule antibodies.
- the one or more anti-immune checkpoint molecule antibodies include at least one monoclonal antibody.
- the one or more immune checkpoint inhibitors include one or more small molecules capable of inhibiting or blocking one or more immune checkpoint molecules.
- small molecule checkpoint inhibitors include CA-170 and CA-327, which both target PD-L1.
- the one or more anti-immune checkpoint molecule antibodies include an anti-CTLA4 antibody, an anti-PD-1 antibody, an anti-PD-Ll antibody, an anti-LAG3 antibody, an anti-KIR antibody, an anti-A2AR antibody, and anti-BTLA antibody, an anti-CD40 antibody, an anti-CD27 antibody, an anti-CD28 antibody, an anti-CD 137 antibody, an anti-OX40 antibody, an anti-OX40L antibody, an anti-GITR antibody, an anti-GITRL antibody, an anti-ICOS antibody, an anti-ICOSL antibody, an anti-B7H3 antibody, an anti-B7H4 antibody, an anti-IDO antibody, an anti-
- TIM-3 antibody an anti-Gal-9 antibody, or an anti-VISTA antibody.
- the TRT agent is metaiodobenzylguanidine (MIBG), where the iodine atom in the MIBG is a radioactive iodine isotope.
- MIBG metaiodobenzylguanidine
- the TRT agent is a radiolabeled tumor-targeting antibody.
- the TRT agent is radioactive isotope of radium, such as
- the TRT agent is a radioactive phospholipid ether metal chelate having the formula:
- Ri includes a chelating agent that is chelated to a metal atom, wherein the metal atom is an alpha, beta or Auger emitting metal isotope with a half-life of greater than 6 hours and less than 30 days; a is 0 or 1; n is an integer from 12 to 30; m is 0 or 1; Y is -H, -OH, -COOH, -COOX, -OCOX, or -OX, wherein X is an alkyl or an aryl; R 2 is -N + H 3 , -N + H 2 Z, -N + HZ 2 , or -N + Z 3 , wherein each Z is independently an alkyl or an aroalkyl; and b is 1 or 2.
- Non-limiting examples of metal isotopes that could be used include Sc-47, Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, Pb-212, or Th-227.
- the chelating agent is 1,4,7, 10-tetraazacy clododecane- 1,4,7-triacetic acid (D03A) or one of its derivatives; l,4,7-triazacyclononane-l,4-diacetic acid (NOD A) or one of its derivatives; l,4,7-triazacyclononane-l,4,7-triacetic acid (NOTA) or one of its derivatives; 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid (DOTA) or one of its derivatives; l,4,7-triazacyclononane, l-glutaric acid-4,7- diacetic acid (NODAGA) or one of its derivatives; 1,4,7, 10-tetraazacy clodecane, l- glutaric acid-4,7,10-triacetic acid (DOTAGA) or one of its derivatives; 1,4,8, 11-
- a is 1 (aliphatic aryl-alkyl chain).
- a is 0 (aliphatic alkyl chain).
- m is 1 (acylphospholipid series). In some such embodiments, n is an integer between 12 and 20. In some embodiments, Y is -OCOX, -COOX or -OX.
- X is -CH2CH3 or -CH3.
- m is 0 (alkylphospholipid series).
- b is 1.
- n is 18.
- R2 is -N + Z 3 .
- each Z is independently -CH2CH3 or -CH 3 .
- each Z is -CH 3 .
- the chelating agent chelated to the metal atom is:
- the radioactive phospholipid ether metal chelate is of the following compounds, wherein the selected compound is chelated to the metal atom:
- the phospholipid ether metal chelate structure in the phospholipid ether metal chelate structure, a is 1, b is 1, m is 0, n is 18, and R2 is -N + (CH3)3.
- the phospholipid ether metal chelate is M600 chelated to the metal atom, such as (but not limited to) 90 Y- M600.
- the TRT agent is a radiohalogenated phospholipid ether having the formula:
- Ri comprises a radioactive halogen isotope; a is 0 or 1; n is an integer from 12 to 30; m is 0 or 1; Y is selected from the group consisting of -H, -OH, -COOH, - COOX, -OX, and -OCOX, wherein X is an alkyl or an arylalkyl; and R2 is selected from the group consisting of -N + H 3 , -N + H 2 Z, -N + HZ 2 , and -N + Z 3 , wherein each Z is independently an alkyl or an aryl.
- the radioactive halogen isotope is 123 1, 124 1, 125 I, 131 I,
- a is 1 and m is 0.
- n is 18.
- R 2 is -N + (CH 3 ) 3 .
- a is 1, m is 0, and n is 18.
- the radioactive halogen isotope is 123 I, 124 I, 125 I, or 131 I (the radiohalogenated phospholipid ether is [ 123 I]- M404, [ 124 I]- M404, [ 125 I]- M404, [ 131 I]- M404, [ 211 At]- M404, [ 76 Br]- M404, or [ 77 Br]- M404).
- the TRT agent, the immunostimulatory agent, or both are administered intravenously.
- the subject is a human.
- Non-limiting examples of the cancers presenting as malignant solid tumors that can be treated using the method include melanoma, neuroblastoma, lung cancer, adrenal cancer, colon cancer, colorectal cancer, ovarian cancer, prostate cancer, liver cancer, subcutaneous cancer, squamous cell cancer of the skin or head or neck, intestinal cancer, retinoblastoma, cervical cancer, glioma, breast cancer, pancreatic cancer, soft tissue sarcoma, Ewings sarcoma, rhabdomyosarcoma, osteosarcoma, Wilms' tumor, and pediatric brain tumors.
- the cancer is treated without administering to the subject an antibody to a tumor antigen that is not a checkpoint molecule.
- an anti-GD2 antibody is not adminstered to the subject.
- the disclosure encompasses the use of a TRT agent and one or more immunostimulatory agents for treating a cancer comprising one or more malignant solid tumors in a subject, as further described above.
- the disclosure encompasses the use of a TRT agent and/or one or more immunostimulatory agents for the manufacture of a medicament treating a cancer comprising one or more malignant solid tumors in a subject, as further described above.
- Fig. 1 shows the chemical structure of the base compound 18- (p-iodophenyl) octadecyl phosphocholine ( M404).
- Fig. 2A is a graph showing that xRT + IT-IC elicits in situ tumor vaccination. More specifically, Fig. 2A shows tumor growth curves that show synergy between xRT and IT-hul4.18-IL2. 71% (22/31) of mice treated with xRT + IT-IC are rendered disease- free.
- Fig. 2B is another graph showing that xRT + IT-IC elicits in situ tumor vaccination. More specifically, Fig. 2B shows Kaplan-Meier survival curves that show synergy between xRT and IT-hul4.18-IL2. 71% (22/31) of mice treated with xRT + IT- IC are rendered disease-free.
- Fig. 2C is another graph showing that xRT + IT-IC elicits in situ tumor vaccination. More specifically, Fig. 2C shows that 90% of the treated mice reject subsequent engraftment with B78 melanoma.
- Fig. 3 is a graph demonstrating concomitant immune tolerance. Primary tumor response is shown. A distant un-treated tumor suppresses response to xRT + IT-IC in a 2- tumor B78 melanoma model, and this suppression can be overcome be radiating the second tumor.
- Fig. 4 is a graph showing that concomitant immune tolerance is due to Tregs. Primary tumor response is shown. A distant un-treated tumor suppresses response to xRT + IT-IC in a 2-tumor B78 melanoma model and this suppression can be overcome by depleting Tregs (using transgenic DEREG mice that express diphtheria toxin receptors on their Tregs, and thus depleting Tregs by administering diphtheria toxin).
- Fig. 5 is an image showing selective uptake of 124 I- M404 by B78 melanoma.
- a mouse bearing a ⁇ 200mm 3 B78 tumor received IV 124 I- M404 and had serial PET/CT scans done.
- This image at 71h shows selective uptake by the tumor with some residual background uptake by the heart and liver.
- Fig. 6 is a graph demonstrating that in situ vaccination can be elicited in the presence of residual levels of molecular targeted radiation therapy (TRT).
- TRT molecular targeted radiation therapy
- Treatment with combined xRT + IT-IC is equally effective in the presence or absence of 3 ⁇ 131 I- M404. This approximates the residual activity of TRT that will be present when we deliver xRT (dO) followed by IT-IC (d6-10), as described in Example 4.
- Fig. 7 shows a time course MRI image of a tumor-bearing mouse following injection of Gd- M600 showing enhancement of the tumor (T) by 24 hours.
- Fig. 8A is a graph showing tumor-specific inhibition of primary tumor response to the combination of local RT+IT-IC by a distant untreated tumor in murine melanoma and pancreatic tumor models.
- GD2+ disialoganglioside-expressing
- primary flank tumor +/- a secondary tumor on the contralateral flank were treated to the primary tumor only, as indicated, with xRT on day "1" and intra-tumor (IT) injection of 50 meg of the anti-GD2 immunocytokine (IC), hul4.18-IL2 (a fusion of anti-GD2 mAb and IL2), on day 6-10.
- IT intra-tumor
- Mean primary tumor volumes are displayed in Fig. 8A. More specifically, Fig. 8A shows that in mice bearing a primary B78 melanoma tumor, the presence of an untreated secondary B78 tumor antagonized primary tumor response to RT+IT-IC. We describe this effect as
- Fig. 8B is another graph showing tumor-specific inhibition of primary tumor response to the combination of local RT+IT-IC by a distant untreated tumor in murine melanoma and pancreatic tumor models.
- GD2+ disialoganglioside-expressing
- primary flank tumor +/- a secondary tumor on the contralateral flank were treated to the primary tumor only, as indicated, with xRT on day "1" and intra-tumor (IT) injection of 50 meg of the anti-GD2 immunocytokine (IC), hul4.18-IL2 (a fusion of anti-GD2 mAb and IL2), on day 6-10.
- IT intra-tumor
- IC anti-GD2 immunocytokine
- hul4.18-IL2 a fusion of anti-GD2 mAb and IL2
- Fig. 8B shows Kaplan-Meier survival curves for mice plus replicate experiments. Nearly all mice were euthanized due to primary tumor progression.
- Fig. 8C is another graph showing tumor-specific inhibition of primary tumor response to the combination of local RT+IT-IC by a distant untreated tumor in murine melanoma and pancreatic tumor models.
- GD2+ disialoganglioside-expressing
- primary flank tumor +/- a secondary tumor on the contralateral flank were treated to the primary tumor only, as indicated, with xRT on day "1" and intra-tumor (IT) injection of 50 meg of the anti-GD2 immunocytokine (IC), hul4.18-IL2 (a fusion of anti-GD2 mAb and IL2), on day 6-10.
- IT intra-tumor
- IC anti-GD2 immunocytokine
- hul4.18-IL2 a fusion of anti-GD2 mAb and IL2
- Fig. 8C shows that in mice bearing a primary Panc02-GD2+ pancreatic tumor, with or without a secondary Panc02-GD2- tumor on the opposite flank, the presence of an untreated Panc02 secondary tumor suppressed the response of a primary Panc02-GD2+ tumor to RT+IT-IC.
- Fig. 8D is another graph showing tumor-specific inhibition of primary tumor response to the combination of local RT+IT-IC by a distant untreated tumor in murine melanoma and pancreatic tumor models.
- GD2+ disialoganglioside-expressing
- primary flank tumor +/- a secondary tumor on the contralateral flank were treated to the primary tumor only, as indicated, with xRT on day "1" and intra-tumor (IT) injection of 50 meg of the anti-GD2 immunocytokine (IC), hul4.18-IL2 (a fusion of anti-GD2 mAb and IL2), on day 6-10.
- IT intra-tumor
- Fig. 8D shows that in mice bearing a primary B78 melanoma tumor, a secondary B78 tumor suppressed primary tumor response to RT+IT-IC but a secondary Panc02-GD2+ pancreatic tumor did not exert this effect.
- Fig. 8E is another graph showing tumor-specific inhibition of primary tumor response to the combination of local RT+IT-IC by a distant untreated tumor in murine melanoma and pancreatic tumor models. C57BL/6 mice bearing a syngeneic,
- GD2+ disialoganglioside-expressing
- primary flank tumor +/- a secondary tumor on the contralateral flank were treated to the primary tumor only, as indicated, with xRT on day "1" and intra-tumor (IT) injection of 50 meg of the anti-GD2 immunocytokine (IC), hul4.18-IL2 (a fusion of anti-GD2 mAb and IL2), on day 6-10.
- IT intra-tumor
- Fig. 8E shows that in mice bearing a primary Panc02-GD2+ tumor a secondary Panc02-GD2- tumor suppressed primary tumor response to combined xRT and IT-hul4.18-IL2, while a B78 secondary tumor did not.
- n number of mice per group.
- NS non-significant, ***p ⁇ 0.001.
- Fig. 9A includes immunohistochemistry images (left and center) and graphs (right) showing that concomitant immune tolerance is circumvented by specific depletion of regulator T cells (Tregs). More specifically, Fig. 9A shows immunohistochemistry for the Treg marker, FoxP3 (representative 400x images are shown) for tumors evaluated on day 6 after xRT in mice with one (Fig. 9A, leftmost panels Al and A2) or two (Fig. 9A ⁇ center panels A3 and A4) tumors. Mice received no xRT, or xRT only to the primary tumor. The primary tumor is shown in Fig. 9A, panels_Al-A3 and the secondary is shown in Fig. 9A a panel A4.
- Fig. 9B is another graph showing that concomitant immune tolerance is circumvented by specific depletion of regulator T cells (Tregs). More specifically, Fig. 9B shows that DEREG mice express diphtheria toxin receptor under control of the Treg- specific FoxP3 promoter, enabling specific depletion of Tregs upon IP injection of diphtheria toxin. DEREG mice bearing primary and secondary B78 melanoma tumors were treated with xRT+IT-IC to the primary tumor and IP injection of either diphtheria toxin or PBS (the first of replicate experiments are shown). Concomitant immune tolerance is eliminated following depletion of Tregs in these mice, resulting in improved (Fig. 9B) primary tumor response.
- Tregs regulator T cells
- Fig. 10A is a graph showing that concomitant immune tolerance is overcome by delivering xRT to both tumor sites.
- the secondary tumor suppresses primary tumor response to primary tumor treatment with xRT + IT-IC. This is overcome by delivering 12 Gy xRT to both the primary and secondary tumors and IT-IC to the primary tumor, resulting in improved (Fig. 10A) primary tumor response (the first of replicate experiments is shown) from replicate experiments.
- n number of mice per group. **p ⁇ 0.01, ***/? ⁇ 0.001.
- Fig. 10B is another graph showing that concomitant immune tolerance is overcome by delivering xRT to both tumor sites.
- the secondary tumor suppresses primary tumor response to primary tumor treatment with xRT + IT-IC. This is overcome by delivering 12 Gy xRT to both the primary and secondary tumors and IT-IC to the primary tumor, resulting in improved (Fig. 10B) aggregate animal survival from replicate experiments.
- n number of mice per group. **p ⁇ 0.0 ⁇ , ***/ 0.001.
- Fig. 11 A is a graph showing that low dose xRT alone does not elicit in situ vaccination but does overcome concomitant immune tolerance when delivered to distant tumor sites together with 12 Gy + IT-IC treatment of an in situ vaccine site. More specifically, Fig. 11 A shows that in mice bearing a primary B78 tumor only, 12 Gy + IT- IC elicits in situ vaccination (as shown previously) and results in complete tumor regression in most mice (4/6 in this experiment) and a memory immune response (Morris, Cancer Res, 2016). On the other hand no animals exhibit complete tumor regression following either IT-IC alone or low dose (2 Gy) xRT + IT-IC (0/6 in both groups) p ⁇ 0.05.
- Fig. 1 IB is another graph showing that low dose xRT alone does not elicit in situ vaccination but does overcome concomitant immune tolerance when delivered to distant tumor sites together with 12 Gy + IT-IC treatment of an in situ vaccine site. More specifically, Fig. 1 IB shows that in mice bearing a primary and secondary B78 melanoma tumor, low dose xRT (2 Gy or 5 Gy) delivered to the secondary tumor is comparable to 12 Gy in its capacity to overcome concomitant immune tolerance at the primary tumor.
- Fig. 11C is another graph showing that low dose xRT alone does not elicit in situ vaccination but does overcome concomitant immune tolerance when delivered to distant tumor sites together with 12 Gy + IT-IC treatment of an in situ vaccine site. More specifically, Fig. 11C shows that in these same animals, it is apparent that overcoming concomitant immune tolerance by delivery of low dose xRT to the secondary tumor rescues a systemic response to IT-IC immunotherapy.
- IT-IC injection of the primary tumor triggers a systemic anti-tumor effect that renders secondary tumor response to 2 Gy or 5 Gy greater than the response to 12 Gy xRT in absence of primary tumor IT-IC injection.
- Fig. 12A is a PET image showing that low dose TRT with 131 I- M404 effectively depletes tumor infiltrating FoxP3+ Tregs without systemic leukopenia or depletion of tumor infiltrating CD8+ effector T cells.
- TRT could be administered systemically to specifically deplete tumor infiltrating suppressive immune cells (Tregs), without triggering systemic immune cell depletion and leukopenia. More specifically, Fig.
- FIG. 12A shows dosimetry studies in this B78 melanoma tumor model using positron-emitting 124 I- M404 confirm tumor- selective uptake of M404.
- C57BL/6 mice bearing B78 tumors were treated with 60 iC 131 I- M404. This activity approximates the amount of 131 I- M404 necessary to deliver ⁇ 2 Gy TRT to a B78 tumor.
- Fig. 12B is a bar graph showing that low dose TRT with 131 I- M404 effectively depletes tumor infiltrating FoxP3+ Tregs without systemic leukopenia or depletion of tumor infiltrating CD8+ effector T cells.
- TRT could be administered systemically to specifically deplete tumor infiltrating suppressive immune cells (Tregs), without triggering systemic immune cell depletion and leukopenia. More specifically, Fig. 12B shows that this dose of TRT did not result in any significant systemic leukopenia ⁇
- Fig. 12C is another bar graph showing that low dose TRT with 131 I- M404 effectively depletes tumor infiltrating FoxP3+ Tregs without systemic leukopenia or depletion of tumor infiltrating CD8+ effector T cells.
- Fig. 12D is another bar graph showing that low dose TRT with 131 I-NM404 effectively depletes tumor infiltrating FoxP3+ Tregs without systemic leukopenia or depletion of tumor infiltrating CD8+ effector T cells.
- TRT could be administered systemically to specifically deplete tumor infiltrating suppressive immune cells (Tregs), without triggering systemic immune cell depletion and leukopenia. More specifically, Fig.
- Fig. 13 A is a graph showing that low dose TRT with 131 I- M404 effectively overcomes concomitant immune tolerance and rescues the systemic anti-tumor effect of in situ vaccination. Given the capacity of low dose 131 I- M404 TRT to deplete tumor- infiltrating Tregs without rendering a mouse leukopenic, we tested whether low dose 13 l l- M404 might effectively overcome concomitant immune tolerance. C57BL/6 mice bearing two B78 tumors were treated with 60-mcCi 131 I- M404 on day 1 ( M404), as indicated.
- mice After one half-life (day 8), animals received 12 Gy xRT or no xRT to the primary tumor (in situ vaccine site). Control mice receiving no 131 I- M404 were treated to the secondary tumor as indicated (0, 2, or 12 Gy). Mice received daily IT injections of IC to the primary tumor (in situ vaccine site), as indicated, on days 13-17. More specifically, Fig. 13 A shows that primary tumor response is shown and demonstrates that administration of low dose TRT effectively overcomes concomitant immune tolerance and rescues the systemic anti-tumor effect of in situ vaccination.
- Fig. 13B is another graph showing that low dose TRT with 131 I- M404 effectively overcomes concomitant immune tolerance and rescues the systemic antitumor effect of in situ vaccination. Given the capacity of low dose 131 I- M404 TRT to deplete tumor-infiltrating Tregs without rendering a mouse leukopenic, we tested whether low dose 131 I- M404 might effectively overcome concomitant immune tolerance.
- C57BL/6 mice bearing two B78 tumors were treated with 60-mcCi 131 I- M404 on day 1 ( M404), as indicated. After one half-life (day 8), animals received 12 Gy xRT or no xRT to the primary tumor (in situ vaccine site). Control mice receiving no 131 I- M404 were treated to the secondary tumor as indicated (0, 2, or 12 Gy). Mice received daily IT injections of IC to the primary tumor (in situ vaccine site), as indicated, on days 13-17. More specifically, Fig. 13B shows that secondary tumor response is shown and demonstrates that administration of low dose TRT effectively overcomes concomitant immune tolerance and rescues the systemic anti-tumor effect of in situ vaccination.
- Figure 14 shows the chemical structure of an exemplary alkylphosphocholine metal chelate ( 64 Cu- M600). Other metals may be used in place of 64 Cu.
- Figure 15 is a PET/CT image of two single tumor B78 mice from a scan taken 48 hours post-injection with 86 Y- M600.
- Figure 16 is a PET/CT image of two two-tumor B78 mice from a scan taken 48 hours post-injection with 86 Y- M600.
- Figure 17 includes PET/CT images for a U87MG mouse from scans taken 3 hours (left panel), 24 hours (center panel) and 48 hours (right panel) post-injection with 64 Cu- M600.
- the images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown on far right).
- Figure 18 includes PET/CT images for a 4T1 mouse from scans taken 3 hours (left panel), 24 hours (center panel) and 48 hours (right panel) post-injection with 64 Cu- M600.
- the images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown on far right).
- Figure 19 includes PET/CT images for an HCT-116 mouse from scans taken 3 hours (left panel), 24 hours (center panel) and 48 hours (right panel) post-injection with 64 Cu- M600.
- the images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown on far right).
- Figure 20 includes PET/CT images for an A549 mouse from scans taken 3 hours (left panel), 24 hours (center panel) and 48 hours (right panel) post-injection with 64 Cu- M600.
- the images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown on far right).
- Figure 21 includes PET/CT images for a PC-3 mouse from scans taken 3 hours (left panel), 24 hours (center panel) and 48 hours (right panel) post-injection with 64 Cu- M600.
- the images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown on far right).
- Figure 22 includes PET/CT images for an HT-29 mouse from scans taken 3 hours (left panel), 24 hours (center panel) and 48 hours (right panel) post-injection with 64 Cu- M600.
- the images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown on far right).
- Figure 23 includes PET/CT images for a MiaPaca mouse from scans taken 3 hours (left panel), 24 hours (center panel) and 48 hours (right panel) post-injection with 64 Cu- M600. The images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown on far right).
- Figure 24 includes PET/CT images for a 4T1 mouse from scans taken 3 hours (left panel), 24 hours (center panel) and 48 hours (right panel) post-injection with 86 Y- M600. The images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown on far right).
- Figure 25 includes PET/CT images for a 4T1 mouse from scans taken 3 hours (left panel), 24 hours (center panel) and 48 hours (right panel) post-injection with 89 Zr- M600.
- the images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown on far right).
- Figure 26 includes PET/CT images for an HT-29 mouse from scans taken 4 hours (left panel) and 1 day (right panel) post-injection with 52 Mn- M600.
- the images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown on far right).
- Figure 27 includes PET/CT images for a PC-3 mouse from scans taken 4 hours (left panel) and 1 day (right panel) post-injection with 52 Mn- M600.
- the images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown to the right of each image).
- Figure 28 includes PET/CT images for an HT-29 mouse from scans taken 2 days (left panel), 3 days (second panel from the left), 5 days (second panel form the right) and 7 days (right panel) post-injection with 52 Mn- M600.
- the images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown to the right of the images).
- Figure 29 includes PET/CT images for a PC-3 mouse from scans taken 2 days (left panel), 3 days (second panel from the left), 5 days (second panel form the right) and 7 days (right panel) post-injection with 52 Mn- M600.
- the images show tissue activity calculated as a percent of injected dose/g tissue (%ID/g, scale shown to the right of the images).
- Figure 30 is a graph showing PET quantitative region of interest data (chelate uptake as a function of time) for 4T1 tumor tissue in 4T1 mice injected with 86 Y-NM600, 64 Cu-NM600 and 89 Zr- M-600.
- Figure 31 is a graph showing PET quantitative region of interest data (chelate uptake as a function of time) for heart tissue in 4T1 mice injected with 86 Y- M600, 64 Cu- M600 and 89 Zr- M-600.
- Figure 32 is a graph showing PET quantitative region of interest data (chelate uptake as a function of time) for liver tissue in 4T1 mice injected with 86 Y- M600, 64 Cu- M600 and 89 Zr- M-600.
- Figure 33 is a graph showing PET quantitative region of interest data (chelate uptake as a function of time) for whole body in 4T1 mice injected with 86 Y-NM600, 64 Cu-NM600 and 89 Zr- M-600.
- Figure 32 is a bar graph illustrating ex vivo chelate biodistribution in healthy and tumor tissues in 4T1 mice 48 hours ( 86 Y- M600, 64 Cu- M600, 89 Zr- M-600 and 177 Lu-NM600) and 96 hours ( 177 Lu- M600) post-injection of the metal chelates.
- Figure 35 shows the chemical structure of an exemplary alkylphosphocholine metal chelate ( 177 Lu- M600). Other metals may be used in place of 177 Lu.
- Figure 36 is an audioradiographic image of three B78 mice taken 48 hours after injection with 90 Y- M600. Xenografted B78 tumors are seen as large dark spots at the lower right of each mouse image.
- Figure 37 is an audioradiographic image of three B78 mice taken 96 hours after injection with 90 Y- M600. Xenografted B78 tumors are seen as large dark spots at the lower right of each mouse image.
- Figure 38 is an audioradiographic image of a B78 mouse taken on day 5 after injection with 177 Lu- M600. Xenografted B78 tumors are seen as two dark spots at the bottom of the mouse image.
- Figure 39 is an audioradiographic image of a B78 mouse taken on day 13 after injection with 177 Lu- M600. Xenografted B78 tumors are seen as two dark spots at the bottom of the mouse image.
- Figure 39 is an audioradiographic image of a B78 mouse taken on day 13 after injection with 177 Lu- M600. Xenografted B78 tumors are seen as two dark spots at the bottom of the mouse image.
- Figure 40 is an audioradiographic image of a MiaPaca mouse taken 10 days after injection with 177 Lu-NM600. The location of the xenografted MiaPaca tumor is indicated by the arrow and dashed circle.
- Figure 41 is an audioradiographic image of three 4T1 mice taken 48 hours after injection with 177 Lu-NM600. The locations of the xenografted 4T1 tumors are indicated by the arrows and dashed circles.
- Figure 42 is an audioradiographic image of three 4T1 mice taken 96 hours after injection with 177 Lu-NM600. The locations of the xenografted 4T1 tumors are indicated by the dashed circles.
- Figure 43 is an audioradiographic image of three 4T1 mice taken 4 hours after injection with 90 Y- M600. The locations of the xenografted 4T1 tumors are indicated by the arrows and dashed circles.
- Figure 44 is an audioradiographic image of three 4T1 mice taken 48 hours after injection with 90 Y- M600.
- the xenografted 4T1 tumors are seen as large dark spots on the lower right of each mouse image.
- Figure 45 is an audioradiographic image of three 4T1 mice taken 96 hours after injection with 90 Y- M600.
- the xenografted 4T1 tumors are seen as large dark spots on the lower right of each mouse image.
- Figure 46 is a graph illustrating the radiotherapeutic effect of 90 Y- M600 at two different doses (150 ⁇ and 300 ⁇ ) in a B78 xenograft mouse model, versus a control (excipient only). Data is presented as measured tumor volume in mm 3 as a function of time in days after injection.
- Figure 47 is a graph illustrating the radiotherapeutic effect of a single 500 ⁇ dose of 177 Lu-NM600 in a B78 xenograft mouse model, versus a control (excipient only). Data is presented as measured tumor volume in mm 3 as a function of time in days after injection.
- Figure 48 is a graph illustrating the radiotherapeutic effect of a single 400 ⁇ dose of 177 Lu- M600 in a MiaPaca xenograft mouse model, versus a control (excipient only). Data is presented as measured tumor volume in mm 3 as a function of time in days after injection.
- Figure 49 is a graph illustrating the radiotherapeutic effect of a single 500 ⁇ ' dose of 177 Lu-NM600 in a 4T1 xenograft mouse model, versus a control (excipient only). Data is presented as measured tumor volume in mm 3 as a function of time in days after injection. * P ⁇ 0.05; ** P ⁇ 0.01; *** P ⁇ 0.001.
- Figure 50 is a graph illustrating the radiotherapeutic effect of two serial doses of 177 Lu-NM600 (500 ⁇ and 250 ⁇ ) in a 4T1 xenograft mouse model, versus a control (excipient only). Data is presented as measured tumor volume in mm 3 as a function of time in days after injection.
- Figure 51 is a graph illustrating the radiotherapeutic effect of 177 Lu- M600 at two different doses (500 ⁇ and 250 ⁇ ) in a 4T1 xenograft mouse model, versus a control (excipient only). Data is presented as measured tumor volume in mm 3 as a function of time in days after injection.
- Figure 52 is a graph illustrating the impact of tumor mass on the comparative therapeutic efficacy of 90 Y- M600 and 131 I- M404 in conventional TRT.
- Figure 53 is a bar graph comparing average albumin binding energies of three different metal chelate analogs of M404, along with an amine analog. For comparison, the binding energy of I- M404 is shown as a dotted line.
- Figure 54 is a graph illustrating tumor volume (mm 3 ) as a function of time (days) in B78 melanoma flank tumor mice treated with anti-CTLA4 immune checkpoint inhibitor (CTLA4) and/or varying doses (25 ⁇ , 50 ⁇ , or 100 ⁇ ) of the targeted radiotherapy (TRT) agent Y90- M600.
- Control mice were administered vehicle without anti-CTLA4 or the TRT agent (PBS).
- combination treatment with 50 or 100 ⁇ of Y90- M600 with anti-CTLA4 had significantly (p ⁇ 0.05 by ANOVA) reduced tumor growth compared to PBS, Y90-NM600 alone, or anti-CTLA4 alone.
- the 25 Y90- M600 combination treatment group with anti-CTLA-4 had an intermediate growth delay response that showed a trend towards dose response.
- Figure 55 is a graph showing aggregate animal survival for mice administered a combination of TRT (50 ⁇ Y90- M600) and checkpoint blockade (anti-CTLA4), compared to mice administered TRT alone, checkpoint blockade alone (anti-CTLA4), or PBS vehicle.
- Figure 56 is a graph showing aggregate animal survival for mice administered three different combinations of TRT (25 ⁇ , 50 ⁇ , and 100 ⁇ Y90- M600) with checkpoint blockade (anti-CTLA4).
- Figure 57 is a graph illustrating tumor volume (mm 3 ) as a function of time (days) in B78 melanoma flank tumor mice treated with anti-CTLA4 immune checkpoint inhibitor (CTLA4) and/or varying doses (25 ⁇ , 50 ⁇ , or 100 ⁇ ) of the molecularly targeted radiotherapy (MTRT) agent 90 Y- M600.
- CTLA4 immune checkpoint inhibitor
- MTRT molecularly targeted radiotherapy
- Control mice were administered vehicle without anti-CTLA4 or the MTRT agent (PBS).
- Combination treatment with 50 or 100 ⁇ of 90 Y-NM600 with anti-CTLA4 had significantly (p ⁇ 0.05 by ANOVA) reduced tumor growth compared to PBS, 90 Y- M600 alone, or anti-CTLA4 alone.
- Figure 58 is a graph showing aggregate animal survival for B78 melanoma flank tumor mice treated with anti-CTLA4 immune checkpoint inhibitor (CTLA4) and/or varying doses (25 ⁇ , 50 ⁇ , or 100 ⁇ ) of the molecularly targeted radiotherapy (MTRT) agent 90 Y- M600.
- CTLA4 immune checkpoint inhibitor
- MTRT molecularly targeted radiotherapy
- Mice administered a combination of MTRT (50 ⁇ 90 Y- M600 or 100 ⁇ 90 Y- M600) and checkpoint blockade (anti-CTLA4) exhibited significantly increased survival as compared to other groups.
- Figure 59 is a graph illustrating tumor volume (mm 3 ) as a function of time (days) in NXS2 neuroblastoma tumor mice treated with anti-CTLA4 immune checkpoint inhibitor (CTLA4) and/or 50 ⁇ of the molecularly targeted radiotherapy (MTRT) agent 90 Y- M600.
- CTLA4 immune checkpoint inhibitor
- MTRT molecularly targeted radiotherapy
- Control mice were administered vehicle without anti-CTLA4 or the TRT agent (PBS).
- PBS TRT agent
- Combination treatment of 90 Y- M600 MTRT with anti-CTLA4 had significantly reduced tumor growth compared to PBS, 90 Y- M600 alone, or anti-CTLA4 alone.
- Figure 60 is a graph illustrating tumor volume (mm 3 ) as a function of time (days) in 4T1 breast cancer tumor mice treated with anti-CTLA4 immune checkpoint inhibitor (CTLA4) and/or 50 ⁇ of the molecularly targeted radiotherapy (MTRT) agent 90 Y- M600.
- CTLA4 immune checkpoint inhibitor
- MTRT molecularly targeted radiotherapy
- Control mice were administered vehicle without anti-CTLA4 or the TRT agent (PBS).
- PBS TRT agent
- Combination treatment of 90 Y- M600 MTRT with anti-CTLA4 had significantly reduced tumor growth compared to PBS, 90 Y- M600 alone, or anti-CTLA4 alone.
- Figure 61 is a graph illustrating tumor volume (mm ) as a function of time (days) for the irradiated primary B78 tumor in B78 melanoma flank tumor mice having both primary and secondary (distant) tumors.
- Mice were treated with various combinations of EBRT of the primary tumor only (12 Gy, secondary tumor was shielded), anti-CTLA4 immune checkpoint inhibitor (CTLA4) and/or 50 ⁇ of the molecularly targeted radiotherapy (MTRT) agent 90 Y- M600.
- CTLA4 anti-CTLA4 immune checkpoint inhibitor
- MTRT molecularly targeted radiotherapy
- Figure 62 is a graph illustrating tumor volume (mm 3 ) as a function of time (days) for the shielded secondary (distant) B78 tumor in B78 melanoma flank tumor mice having both primary and secondary tumors.
- Mice were treated with various combinations of EBRT of the primary tumor only (12 Gy, secondary tumor was shielded), anti-CTLA4 immune checkpoint inhibitor (CTLA4) and/or 50 ⁇ of the molecularly targeted radiotherapy (MTRT) agent 90 Y-NM600.
- CTLA4 anti-CTLA4 immune checkpoint inhibitor
- MTRT molecularly targeted radiotherapy
- the disclosure is inclusive of the compounds described herein (including intermediates) in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), tautomers, salts, solvates, polymorphs, prodrugs, and the like.
- isomers e.g., diastereomers and enantiomers
- tautomers e.g., tautomers
- salts e.g
- “Pharmaceutically acceptable” as used herein means that the compound or composition or carrier is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the necessity of the treatment.
- the term "effective amount,” as used herein, refers to the amount of the compounds or dosages that will elicit the biological or medical response of a subject, tissue or cell that is being sought by the researcher, veterinarian, medical doctor or other clinician.
- pharmaceutically-acceptable carrier includes any and all dry powder, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like.
- Pharmaceutically-acceptable carriers are materials, useful for the purpose of administering the compounds in the method of the present invention, which are preferably non-toxic, and may be solid, liquid, or gaseous materials, which are otherwise inert and pharmaceutically acceptable, and are compatible with the compounds of the present invention.
- Such carriers include, without limitation, various lactose, mannitol, oils such as corn oil, buffers such as PBS, saline, polyethylene glycol, glycerin, polypropylene glycol, dimethylsulfoxide, an amide such as dimethylacetamide, a protein such as albumin, and a detergent such as Tween 80, mono- and oligopolysaccharides such as glucose, lactose, cyclodextrins and starch.
- buffers such as PBS, saline
- polyethylene glycol glycerin
- polypropylene glycol dimethylsulfoxide
- dimethylsulfoxide dimethylsulfoxide
- an amide such as dimethylacetamide
- a protein such as albumin
- a detergent such as Tween 80
- mono- and oligopolysaccharides such as glucose, lactose, cyclodextrins and starch.
- administering refers to providing the compound or pharmaceutical composition of the invention to a subject suffering from or at risk of the diseases or conditions to be treated or prevented.
- a route of administration in pharmacology is the path by which a drug is taken into the body. Routes of administration may be generally classified by the location at which the substance is applied. Common examples may include oral and intravenous administration. Routes can also be classified based on where the target of action is.
- Action may be topical (local), enteral (system-wide effect, but delivered through the gastrointestinal tract), or parenteral (systemic action, but delivered by routes other than the GI tract), via lung by inhalation.
- the desired effect is systemic (non-local), substance is given via the digestive tract.
- the desired effect is systemic, and substance is given by routes other than the digestive tract.
- Enteral administration may be administration that involves any part of the gastrointestinal tract and has systemic effects.
- the examples may include those by mouth (orally), many drugs as tablets, capsules, or drops, those by gastric feeding tube, duodenal feeding tube, or gastrostomy, many drugs and enteral nutrition, and those rectally, various drugs in suppository.
- parenteral administrations may include intravenous (into a vein), e.g. many drugs, total parenteral nutrition intra-arterial (into an artery), e.g., vasodilator drugs in the treatment of vasospasm and thrombolytic drugs for treatment of embolism, intraosseous infusion (into the bone marrow), intra-muscular, intracerebral (into the brain parenchyma), intracerebroventricular (into cerebral ventricular system), intrathecal (an injection into the spinal canal), and subcutaneous (under the skin).
- intraosseous infusion is, in effect, an indirect intravenous access because the bone marrow drains directly into the venous system.
- Intraosseous infusion may be
- ADCC Antibody dependent cell-mediated cytotoxicity
- Panc02-GD2 A pancreatic cancer syngeneic to C57B1/6 mice, expressing GD2, due to transfection with GD2 synthase; PLE, Phospholipid ether; RT, Radiation therapy; TRT, Targeted radiotherapy; W, week; 9464D-GD2, A neuroblastoma syngeneic to C57B1/6 mice, expressing GD2, due to transfection with GD2 synthase.
- This disclosure is directed to methods of treating any cancer that presents as one or more malignant solid tumors.
- the disclosed methods combine two treatment steps, with an unexpected synergy resulting in a much improved effect against the malignant solid tumors.
- an immunomodulatory dose of a radioactive phospholipid metal chelate compound or radiohalogenated phospholipid compound that is differentially taken up by and retained within malignant solid tumor tissue is
- a composition that includes one or more agents capable of stimulating specific immune cells, either with or without additional xRT to at least one of the malignant solid tumors being treated with immune-stimulating agents.
- the immunomodulatory dose of the radioactive phospholipid metal chelate or radiohalogenated compound likely reduces Treg levels (and other immune-suppressive elements) and prevents the immune system dampening (concomitant immune tolerance) that occurs when xRT is used against a tumor and one or more additional tumors are not radiated, although an understanding of the mechanism is not necessary to practice the invention and the invention is not limited to any particular mechanism of action.
- inhibitors as exemplary immunostimulatory agents.
- systemically-administered immunotherapy is performed by administering an immunostimulatory agent systemically.
- the immunostimulatory agent circulates through the whole body of the subject, stimulating the body's natural immune response.
- Immune checkpoint inhibitors are non-limiting examples of such
- Activated T cells express multiple immune co-inhibitory receptors, such as lymphocyte-activation gene 3 (LAG-3), programmed cell death protein 1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4).
- LAG-3 lymphocyte-activation gene 3
- PD-1 programmed cell death protein 1
- CTL4 cytotoxic T-lymphocyte-associated protein 4
- cancer growth is partly mediated by immune suppression induced by cancers.
- Tumors can activate suppressive immune checkpoint pathways in order to diminish the general immune response to the tumor. Accordingly, blockade of key immune checkpoint pathways can induce anti-tumor immunity, facilitated by the patient's own immune system.
- CTLA4 was the first immune checkpoint molecule to be clinically targeted, by administering CTLA4-targeting (anti-CLA4) mAbs.
- anti-CLA4 anti-CLA4
- the most promising immune checkpoint inhibitor strategies for the treatment of cancers involve administering mAbs targeting CTLA-4 and/or PD-1/PD-L1.
- Other immune checkpoint inhibitor strategies are currently in development, and the disclosed combination method is not limited to targeting any specific immune checkpoint pathway.
- the radioactive phospholipid metal chelate compound used should selectively target a wide range of solid tumor cell types, such that the RT emitted by the metal isotope chelated to the metal chelate compound is directed to malignant solid tumor tissue without substantially exposing other tissue types to the emitted RT.
- the radioactive metal isotope included in the radioactive phospholipid metal chelate compound may be any radioactive metal isotope known to emit ionizing RT in a form that would result in immunostimulation of the cells that take up the compound.
- Radioactive metal isotopes that could be used include Lu-177, Y-90, Ho-166, Re-186, Re- 188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, Pb-212, or Th-227.
- the immunomodulatory RT dose (as opposed to injected dose) of the radioactive phospholipid metal chelate compound is much less than the dose that would be used for conventional RT against malignant solid tumors. Specifically, the dose should be sufficient to stimulate a response in immune cells within the tumor
- the proper immunomodulatory dose can be calculated from imaging data obtained after administering a "detection-facilitating" dose of a radioactive metal chelate compound.
- the detection-facilitating dose may be quite different than the
- radioactive metal isotope that is chelated into the radioactive metal chelate compound may be different (although the rest of the compound structure should be the same).
- the radioactive metal isotope used in the detection step and dosimetry calculations may be any radioactive metal isotope known to emit RT in a form that is readily detectable by conventional imaging means.
- Non-limiting examples of "conventional imaging means" include gamma ray detection, PET scanning, and SPECT scanning.
- Non-limiting examples of radioactive metal isotopes that could be used include Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Ga-67, In-I l l, or Tc-99m.
- the disclosed structures utilize an alkylphosphocholine (APC) carrier backbone. Once synthesized, the agents should harbor formulation properties that render them suitable for injection while retaining tumor selectivity as was demonstrated previously with the related radiohalogenated compounds.
- the disclosed structures include a chelating moiety to which the radioactive metal isotope will chelate to produce the final imaging or therapeutic agent.
- NOTA-NM404 conjugates can be synthesized in an analogous manner.
- any route of administration may be suitable.
- the disclosed alkylphosphocholine analogs may be administered to the subject via intravenous injection.
- the disclosed alkylphosphocholine analogs may be administered to the subject via intravenous injection.
- alkylphosphocholine analogs may be administered to the subject via any other suitable systemic deliveries, such as parenteral, intranasal, sublingual, rectal, or transdermal administrations.
- the disclosed alkylphosphocholine analogs may be administered to the subject via nasal systems or mouth through, e.g., inhalation.
- the disclosed alkylphosphocholine analogs may be administered to the subject via intraperitoneal injection or IP injection.
- the disclosed alkylphosphocholine analogs may be provided as pharmaceutically acceptable salts.
- Other salts may, however, be useful in the preparation of the alkylphosphocholine analogs or of their pharmaceutically acceptable salts.
- Suitable pharmaceutically acceptable salts include, without limitation, acid addition salts which may, for example, be formed by mixing a solution of the
- alkylphosphocholine analog with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
- a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
- the disclosed alkylphosphocholine analogs may accordingly exist as enantiomers. Where the disclosed alkylphosphocholine analogs possess two or more asymmetric centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present disclosure.
- compositions comprising one or more of the disclosed alkylphosphocholine analogs in association with a pharmaceutically acceptable carrier.
- these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
- the principal active ingredient is mixed with a pharmaceutically acceptable carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture for a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- a pharmaceutically acceptable carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture for a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- preformulation compositions When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
- Typical unit dosage forms contain from 1 to 100 mg, for example, 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
- the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer which, serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- the liquid forms in which the alkylphosphocholine analogs may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium caboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
- injectable and infusion dosage forms include, but are not limited to, liposomal injectables or a lipid bilayer vesicle having phospholipids that encapsulate an active drug substance. Injection includes a sterile preparation intended for parenteral use.
- Emulsion injection includes an emulsion comprising a sterile, pyrogen-free preparation intended to be administered parenterally.
- Lipid complex and powder for solution injection are sterile preparations intended for reconstitution to form a solution for parenteral use.
- Powder for suspension injection is a sterile preparation intended for reconstitution to form a suspension for parenteral use.
- Powder lyophilized for liposomal suspension injection is a sterile freeze dried preparation intended for reconstitution for parenteral use that is formulated in a manner allowing incorporation of liposomes, such as a lipid bilayer vesicle having phospholipids used to encapsulate an active drug substance within a lipid bilayer or in an aqueous space, whereby the formulation may be formed upon reconstitution.
- Powder lyophilized for solution injection is a dosage form intended for the solution prepared by lyophilization ("freeze drying"), whereby the process involves removing water from products in a frozen state at extremely low pressures, and whereby subsequent addition of liquid creates a solution that conforms in all respects to the requirements for injections.
- Powder lyophilized for suspension injection is a liquid preparation intended for parenteral use that contains solids suspended in a suitable fluid medium, and it conforms in all respects to the requirements for Sterile Suspensions, whereby the medicinal agents intended for the suspension are prepared by lyophilization.
- Solution injection involves a liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.
- Solution concentrate injection involves a sterile preparation for parenteral use that, upon addition of suitable solvents, yields a solution conforming in all respects to the requirements for injections.
- Suspension injection involves a liquid preparation (suitable for injection) containing solid particles dispersed throughout a liquid phase, whereby the particles are insoluble, and whereby an oil phase is dispersed throughout an aqueous phase or vice-versa.
- Suspension liposomal injection is a liquid preparation (suitable for injection) having an oil phase dispersed throughout an aqueous phase in such a manner that liposomes (a lipid bilayer vesicle usually containing phospholipids used to encapsulate an active drug substance either within a lipid bilayer or in an aqueous space) are formed.
- Suspension sonicated injection is a liquid preparation (suitable for injection) containing solid particles dispersed throughout a liquid phase, whereby the particles are insoluble.
- the product may be sonicated as a gas is bubbled through the suspension resulting in the formation of microspheres by the solid particles.
- the parenteral carrier system includes one or more pharmaceutically suitable excipients, such as solvents and co-solvents, solubilizing agents, wetting agents, suspending agents, thickening agents, emulsifying agents, chelating agents, buffers, pH adjusters, antioxidants, reducing agents, antimicrobial preservatives, bulking agents, protectants, tonicity adjusters, and special additives.
- pharmaceutically suitable excipients such as solvents and co-solvents, solubilizing agents, wetting agents, suspending agents, thickening agents, emulsifying agents, chelating agents, buffers, pH adjusters, antioxidants, reducing agents, antimicrobial preservatives, bulking agents, protectants, tonicity adjusters, and special additives.
- a key limitation is that if there is another macroscopic tumor present in these animals when they receive xRT+ mAb/IL2 treatment to the primary (first) tumor, the second tumor will continue to grow and, to our surprise, suppress the immune response, preventing any shrinkage of the 1 st treated tumor.
- This "concomitant immune tolerance” results, in part, from suppressive regulatory T cells (Tregs) in the 2 nd tumor. Delivering RT alone to both tumors has minimal anti-tumor effect, but does deplete these Tregs.
- Tregs suppressive regulatory T cells
- xRT cannot typically be delivered to all metastatic sites without prohibitive normal tissue toxicity and immune suppression. Yet not delivering xRT to all sites of macroscopic disease may leave inhibitory immune lineages intact, which are capable of suppressing the immunologic response to our local xRT + mAb/IL2 immunotherapy. What is needed, therefore, is a means to deliver RT to all tumor sites in a cancer patient in a targeted manner.
- TRT vehicles capable of targeting systemically administered RT to both primary and metastatic cancers.
- TRT agent 131 I- M404, an intravenously (IV) administered phospholipid ether (PLE) analog
- IV intravenously
- PLE phospholipid ether
- TRT Agents may immuno- modulate all tumors regardless of anatomic location, overcoming concomitant tolerance, which will result in a long-term in situ tumor vaccination effect following local xRT followed by injection of a tumor specific mAb + IL2.
- this combination strategy provides an expanded approach for any tumor type that can be targeted by a tumor-reactive mAb. Furthermore, the approach can be readily generalized to all in situ tumor vaccination strategies.
- iodine in 131 I- M404 can be substituted with chelators capable of carrying a wide variety of metallic imaging (MRI and PET) and TRT radiotherapy moieties.
- MRI and PET metallic imaging
- TRT radiotherapy moieties we describe how to assess the ability of 131 I- M404 (and thus, the related metal chelate analogs) to initiate the systemic immunomodulatory response necessary to enable combined xRT + immunotherapy treatment to induce a potent radioimmune-facilitated response against cancerous solid timuors.
- a similar approach can be used for combined PLE analog-delivered TRT with other immunotherapy methods used against cancerous solid tumors.
- the combination method can use an immunodulation step that is quite different from local in situ tumor vaccination: the systemic administration of an immunostumulatory agent such as an immune checkpoint inhibitor.
- Example 1 we present background data from our B78 GD2+ model in support of the method.
- Example 2 we provide guidance for determining the dose of xRT needed for optimal in situ vaccine effect to a primary tumor, and the lowest dose of xRT to a distant tumor needed to prevent concomitant immune tolerance.
- Example 3 we provide guidance for determining the 131 I- M404 dosing that approximates the required dosing of xRT to metastases, as determined in Example 2, and subsequently evaluating the effects of that 131 I- M404 dose on in vivo immune function. Such guidance can be similarly applied when using the disclosed radioactive phospholipid metal chelate compounds as the TRT agent.
- Example 4 we provide guidance for using data from Examples 2 and 3 to design/test/develop a regimen of 131 I- M404 + local xRT + IT-mAb/IL2 in mice bearing two or more tumors in order to destroy the locally treated tumors and induce T-cell mediated eradication of all distant tumors.
- Critical issues of TRT and xRT dose and time are optimized for antitumor efficacy. Again, such guidance can be similarly applied when using the disclosed radioactive phospholipid metal chelate compounds as the TRT agent.
- Example 5 we provide an exemplary synthesis that also finds use to the synthesis of analogous compounds chelating radioactive metal isotopes.
- Example 6 we demonstrate that an analog having a chelating agent and chelated metal substituted for the iodine moiety of M404 (Gd- M600) is taken up by (and can be imaged in) solid tumor tissue, thus providing proof of concept for using the disclosed metal chelates as a TRT agent.
- Example 13 we discuss how dosimetry in combination with known radiosensitivities can be used by the skilled artisan to optimize treatment dosages for any solid tumors.
- alkylphosphocholine metal chelates in the disclosed methods, rather than the iodinated compounds exemplified in Examples 1-4 and 7-10.
- TRT in combination with systemically-administered immunotherapy, rather than in situ vaccination, is also effective is treating solid tumors.
- the immunostimulatory agent that is systemically administered may be an immune checkpoint blocker or inhibitor (in this case, anti- CTLA4).
- Radioiodinated M404 (1-124 and 1-131), which has now been evaluated in five phase 1 and 2 PET imaging trials and three phase 1 TRT radiotherapy trials, respectively, affords similar tumor uptake and retention properties in over a dozen human cancer types [8].
- Excellent tumor uptake in the cancer models relevant to these examples (the B78 GD2+ murine melanoma) have been confirmed with 124 I- M404 PET imaging (Fig. 5).
- TRT myelo/immunosuppressive. This is why we are pursuing TRT in Examples 3 and 4. Even though it is targeted, TRT does have some systemic delivery of RT. In order to minimize the systemic immune suppression from TRT, we wish to give as low of a dose of TRT as is needed to effectively inhibit the tumor-induced immune tolerance, while not causing systemic RT-induced global immune suppression. Therefore, it is best to select the lowest dose of xRT needed to be delivered to the distant tumor in order to enable a higher xRT dose to the first tumor to function as an in situ vaccine when combined with IT-IC to the first tumor.
- mice bearing a 200 mm 3 first B78 tumor and a -50 mm 3 second B78 tumor will receive 12 Gy of xRT to the first tumor on day-0 ( ⁇ 5 weeks after implantation of the first B78 tumor). This will be followed by our standard regimen of IT-IC on days 6-10. Separate groups of mice will receive varying doses of xRT to the second tumor. Based on data from the lab of B. Johnson
- 131 I- M404 has shown selective uptake in vitro in >95% of tumor lines (human and mouse), with poor uptake by non-malignant cells, and with similar tumor specificity seen in vivo. This includes selective uptake in vivo with the B78 tumor (Fig. 5).
- Fig. 5 the B78 tumor
- TRT tumor-induced tolerance at all sites of distant disease.
- xRT which delivers all dose in minutes and is then done
- TRT deposits dose over time, depending upon both the biological and physical half-life of the targeted isotope (8 day t1 ⁇ 2 for 131 I).
- TRT tumor-induced immune tolerance
- Example 4 Developing an optimal Regimen of 131 I-NM404 + local xRT + IT- mAb IL2 in Mice Bearing Two or More Tumors
- Examples 2 and 3 will provide the information we need to optimize TRT dosing and timing required for efficacy in our 2-tumor model.
- C57BL/6 mice will be inoculated with B78 in the left (L) and right (R) flanks simultaneously. Each tumor should be ⁇ 50 mm 3 after two weeks and ⁇ 200 mm 3 after five weeks. If we assume that our dosimetry calculations in Example 3 suggest that we need to deliver 60 ⁇ of TRT to approximate 3 Gy RT to the second tumor (to block the immune tolerance), our external beam xRT studies predict that this dose should have minimal slowing effect on tumor growth. We would plan to treat different groups of mice with 30, 60 or 90 ⁇ at the 2 w time point (when the tumors are ⁇ 50 mm 3 ).
- the tumors should be ⁇ 200 mm 3 ; at that time we will give xRT (dose determined as outlined in Example 2) followed six days later ( ⁇ 28 d after the TRT) by five daily injections of IT-IC to the tumor in the L flank, to induce the in situ vaccine effect.
- Control mice would get no TRT, and only the xRT and IT-IC to the L flank, anticipating no in situ vaccine due to tolerance from the distant tumor.
- a separate group would get local xRT to both tumors and IT-IC to the L flank, anticipating eradication of both tumors via the in situ vaccine effect.
- Another group get TRT + IT-IC, but without local xRT, anticipating an incomplete vaccine effect.
- Example 4 is most analogous to the relevant clinical setting; namely, patients with an injectable tumor that could be used as an in situ vaccine site, but with multiple distant metastases that could each be causing tumor-induced immune tolerance. These studies will replicate the conditions found to be most effective in the first part of Example 4 (above). The important difference is that these subject will each have four separate tumors, in L and R flanks, and L and R para-scapular regions. The TRT is given at the dose and timing found most effective in the studies outlined in the first section of Example 4, with xRT + IT-IC subsequently given only to the L-flank lesion.
- TRT dose and timing issues to enable most effective in situ vaccine, because the TRT would effectively eliminate the tumor-induced immune tolerance caused by the three sites not getting xRT.
- the measure of efficacy is elimination of all four tumors in most subjects. Modifications in TRT dose and timing are tested in order to generate an optimized regimen that is most effective. Such a regimen finds use in the clinic for patients with multiple distant metastases, that could not all be irradiated via external beam, but could be irradiated via TRT, when combined with local xRT + IT-IC to the "in situ vaccine" site.
- Example 5 Synthesis of metal chelated NM600
- nude athymic mouse with a flank A549 tumor (non small cell lung cancer) xenograft was scanned.
- the Gd-NM600 agent (2.7 mg) was delivered via tail vein injection. Mice were anesthetized and scanning performed prior to contrast administration and at 1, 4, 24, 48, and 72 hours following contrast delivery. Imaging was performed on a 4.7T Varian preclinical MRI scanner with a volume quadrature coil.
- Example 7 Experiments determining the dose of xRT needed for optimal in situ vaccine effect to a primary tumor, and the lowest dose of xRT to a distant tumor needed to prevent concomitant immune tolerance
- lymphoid cells are much more sensitive to low-dose RT than are typical solid tumor cells, and suggest that selective uptake of TRT in tumor may enable intratumor lymphoid cell depletion without systemic lymphopenia.
- lymphoid tumor could serve as an in vivo biological "dosimeter" for identifying and monitoring the effect of TRT on intratumor lymphoid cells.
- a second approach involved treating mice with B78 tumors with these same doses of m I-NM404. These animals were then sacrificed at half-life (8d) intervals, and after sufficient delay for radioactive decay, the tumors were stained for the presence of effector T cells and Tregs by immunohistochemistry Intriguingly, the animals receiving 1 1 I-NM404 in this initial experiment showed no systemic lymphopenia at any time point (by peripheral complete blood count) but did show a decrease in intratumor FoxP3+ Tregs at 2 half-lifes following TRT administration. At this 2-half-life time point, we also observed a decrease in intratumor effector CD8+ T cells.
- Example 9 Experiments using data from Examples 5 and 6 to develop a regimen of 131 I-NM404 + local xRT + IT-mAb/IL2 in mice bearing two or more tumors and induce T-cell mediated eradication of all distant tumors
- This Example illustrates treating animals bearing tumors in at least 2 locations.
- Our strategy involves using xRT and local IT-IC at the in situ vaccine site, in combination with TRT systemically to inhibit CIT, in order to obtain enhanced anti-tumor immune activity at all tumor sites.
- Critical issues of TRT and xRT dose and timing will be optimized for antitumor efficacy.
- mice bearing 2 separate B78 tumors received the estimated required systemic 1 1 ⁇ - NM404 dose followed by xRT and local immunotherapy to the in situ vaccine site. With appropriate controls, this dose of 1 1 I-NM404 did appear to attenuate CIT, as desired in mice with 2 tumors. In addition, in mice with one tumor, this TRT dose did not appear to interfere with the local in situ vaccine effect (as hypothesized and desired). Further testing, and modification of some of the experimental variables, is underway in order to try to maximize the desired effect of blocking CIT without suppressing the in situ vaccine effect. More details regarding these experiments are disclosed in Example 10 below.
- Example 10 Data from mice bearing two or more tumors
- mice bearing a syngeneic, GD2+ primary flank tumor +/- a secondary tumor on the contralateral flank were treated to the primary tumor only, as indicated, with xRT on day "1" and IT injection of 50 meg of the anti-GD2 IC, hul4.18- IL2 on day 6-10.
- mice bearing a primary Panc02-GD2+ pancreatic tumor, with or without a secondary Panc02-GD2- tumor on the opposite flank the presence of an untreated Panc02 secondary tumor suppressed the response of a primary Panc02-GD2+ tumor to xRT+IT-IC ( Figure 8C).
- a secondary B78 tumor suppressed primary tumor response to xRT+IT-IC but a secondary Panc02- GD2+ pancreatic tumor did not exert this effect (Figure 8D).
- mice bearing a primary Panc02-GD2+ tumor a secondary Panc02-GD2- tumor suppressed primary tumor response to combined xRT and IT-hul4.18-IL2, while a B78 secondary tumor did not (Figure 8E).
- Tregs regulator T cells
- mice bearing primary and secondary B78 tumors the secondary tumor suppresses primary tumor response to primary tumor treatment with xRT + IT-IC. This is overcome by delivering 12 Gy xRT to both the primary and secondary tumors and IT-IC to the primary tumor, resulting in improved primary tumor response (Figure 10A) and aggregate animal survival (Figure 10B) from replicate experiments.
- TRT tumor infiltrating suppressive immune cells
- NM600 chelated with four different metals in a range of solid tumors in vivo, as demonstrated by PET/CT imaging of such tumors.
- TRT agents for eliminating tumor- induced immune tolerance, as disclosed herein.
- the structure of NM600 is shown in Figure 14, as an example species chelated with 64 Cu ( 64 Cu-NM600); however, any metal can be readily chelated to NM600.
- mice were each xenografted with one of eight different solid tumor cell lines (B78 (melanoma), U87MG (glioblastoma), 4T1 (breast carcinoma), HCT-116 (colorectal carcinoma), A549 (lung carcinoma), PC-3 (prostate carcinoma), HT-29 (colorectal adenocarcinoma), or MiaPaca (pancreatic carcinoma).
- solid tumor cell lines B78 (melanoma), U87MG (glioblastoma), 4T1 (breast carcinoma), HCT-116 (colorectal carcinoma), A549 (lung carcinoma), PC-3 (prostate carcinoma), HT-29 (colorectal adenocarcinoma), or MiaPaca (pancreatic carcinoma).
- B78 melanoma
- U87MG glioblastoma
- 4T1 breast carcinoma
- HCT-116 colonrectal carcinoma
- A549 lung carcinoma
- PC-3 prostate carcinoma
- HT-29 colonrectal adeno
- NM600 radiolabeled with Cu, Zr, Y, or Mn via lateral tail vein injection was NM600 radiolabeled with Cu, Zr, Y, or Mn via lateral tail vein injection.
- PET imaging was performed in an Inveon micro PET/CT.
- mice were anesthetized with isoflurane (2%) and placed in a prone position in the scanner.
- Longitudinal 40-80 million coincidence event static PET scans were acquired at 3, 12, 24, and 48 hours post-injection of the radiotracer and the images were reconstructed using an OSEM3D/MAP reconstruction algorithm.
- Figure 15 shows the resulting images 48 hours post-injection-for single- tumor B78 mice injected with 86 Y-NM600;
- Figure 16 shows the resulting images 48 hours post-injection-for two-tumor B78 mice injected with 86 Y-NM600;
- Figure 17 shows the resulting images 3, 24 and 48 hours post-injection for a U87MG mouse injected with 64 Cu-NM600;
- Figure 18 shows the resulting images 3, 24 and 48 hours post-injection for a 4T1 mouse injected with 64 Cu-NM600;
- Figure 19 shows the resulting images 3, 24 and 48 hours post-injection for an HCT-116 mouse injected with 64 Cu-NM600;
- Figure 20 shows the resulting images 3, 24 and 48 hours post- injection for an A549 mouse injected with 64 Cu-NM600;
- Figure 21 shows the resulting images 3, 24 and 48 hours post-injection for a PC-3 mouse injected with Cu-NM600;
- Figure 22 shows the resulting images 3, 24 and 48 hours post-injection for
- the scanned mice produced PET/CT three- dimensional volume renderings showing cumulative absorbed dose distribution concentrated in the xenografted tumor.
- the results confirm the differential uptake of metal chelated NM600 into the xenografted solid tumor tissue, and demonstrate the potential use of NM600 analogs incorporating radioactive metal isotopes in the disclosed treatment methods.
- Quantitative region-of-interest analysis of the images was performed by manually contouring the tumor and other organs of interest. Quantitative data was expressed as percent injected doe per gram of tissue (%ID/g). Exemplary data show that 4T1 tumor tissue increased its uptake over time and effectively retained all three tested NM600 chelates ( 86 Y-NM600, 64 Cu-NM600 and 89 Zr-NM600, see Figure 30), while healthy heart (Figure 31), liver ( Figure 32) and whole body tissue (Figure 33) all exhibited significantly decreased uptake/retention over time.
- mice were administered therapeutic doses (250-500 ⁇ (3 ⁇ 4 of 90 Y-NM600, 177 Lu-NM600, or a control solution via lateral tail vein injection.
- Tumor response was assessed by comparing tumor growth of the treated vs. control mice. Tumor volume was determined by measuring tumor's length and width with calipers and calculating the volume using the formula for the volume of the ellipsoid. Mice weight was also recorded. Humane endpoints were defined as: tumor volume >2500 m 3 or significant weight lost below 13 g.
- the diapeutic property of NM600 that 64 Cu/ 86 Y-NM600 can be used as an imaging surrogate for therapeutic metals 177 Lu/ 90 Y-NM600, respectively, was leveraged to estimate tumor dosimetry.
- 64 Cu/ 86 Y-NM600 PET/CT was used to quantitatively measure in vivo biodistribution and estimate radiation dosimetry which can help identify dose limiting organs and potential tumor efficacy of 177 Lu/ 90 Y-NM600 TRT.
- the general concept is as follows: (1) the concentration of 64 Cu/ 86 Y- NM600 within the tumor is quantified over time using longitudinal PET/CT imaging, (2) the concentration of 64 Cu/ 86 Y-NM600 is decay corrected to account for the difference in decay rates between the 64 Cu/ 86 Y-NM600 and 177 Lu/ 90 Y-NM600, (3) the concentration of 177 Lu/ 90 Y-NM600 within the tumor is time-integrated to compute the cumulative activity, or total number of decays, (4) the deposition of the radionuclide decays is modeled within the tumor and quantified.
- Steps (1) through (3) can be performed with any medical image processing software package whereas step (4) requires sophisticated radiation dosimetry software.
- OLINDA/EXM (Stabin, Sparks and Crowe 2005) is a dosimetry estimation software with 510(k) approval that uses the formalism developed by the Medical Internal Radiation Dose (MIRD) committee of the Society for Nuclear Medicine (Bolch et al, 2009).
- MIRD Medical Internal Radiation Dose
- the MIRD approach estimates the mean absorbed dose received by a tissue or organ due to the radiation emitted from within the organ itself or from another source organ.
- D (t - s) A s S(t - s), gives the absorbed dose, D [mGy], to a target region t from the radionuclide activity within a source region s.
- the radionuclide activity of s is expressed as a cumulated activity A s which is the total number of radionuclide decays given in units of MBq-s.
- the S-factor, S(t ⁇ - s) [mGy/ MBq-s] is the fraction of the energy released by one radionuclide decay within the source region s which is deposited within the target region t normalized by the mass of the target region t, m t .
- the S-factor is a tabulated value calculated using Monte Carlo in a set of standard phantoms and organs.
- OLINDA/EXM models the tumor as an isolated unit density sphere whose volume was estimated from the tumor region of interest (ROI) created as part of step (1).
- the concentration of NM600 (%ID/g) within the tumor was determined at each time point and decay corrected. Cumulative activity was then calculated by integrating the concentrations over all time using trapezoidal piecewise integration.
- Intrinsic radiosensitivity is a crucial factor underlying radiotherapy response; and, knowing it a priori for a cancer type could help predict how it may respond to radiation from TRT.
- radiosensitivity is measured as the surviving fraction (between 0 and 1) following irradiation with 2 Gy (SF2) by clonogenic assay.
- the relative radiosensitivity of cancer cell phenotypes ranges from those that have very low radiosensitivities (pancreas, colorectal, glioma and breast) to those with high radiosensitivities (lymphomas). Cancers can be categorized or ranked by their radiosensitivity indices (Table 2).
- alkylphosphocholine metal chelates in place of radioiodinated compounds, such as those exemplified in Examples 1-4 and 7-10
- Chelates permit the use of a wide variety of stable or radioactive metal ions for imaging and therapy. They can be conjugated with a wide variety of alpha, beta, Auger, gamma and positron emitters whereas iodine is limited to one positron (1-124), one beta (1-131), one gamma (1-123) and 1 Auger (1-125) isotope.
- Metal Isotopes are diapeutically more efficacious than 1-131 and 1-124.
- Lu-177 has fewer high energy gammas which make it more favorable for SPECT imaging and dosimetry. However, its beta energy is slightly less than 1-131, making it more ideal for treating smaller tumors.
- Lu-177 are comparable in therapeutic efficacy "horse power", but there is significantly less contribution to the overall dose from gamma-emissions for Lu-177. In the case of Y-90, there is negligible contribution to the radiation dose from gamma-emissions.
- the Committee on Medical Internal Radiation Dose develops standard methods, models, assumptions, and mathematical schema for assessing internal radiation doses from administered radiopharmaceuticals.
- the MIRD approach which simplifies the problem of assessing radiation dose for many different radionuclides, has been implemented in the widely used 510(k) approved software, OLINDA/EXMl.
- OLINDA/EXM has a Spheres Model which can be used to approximate tumor doses.
- the Spheres Model assumes homogeneous distribution of a radiopharmaceutical within unit-density spheres of a range of tumor masses (0.01 - 6,000 g).
- APC chelates are too large to fit into known albumin binding pockets in the plasma and therefore exhibit different in vivo pharmacokinetic and biodistribution profiles (see Figure 53). Lower binding energies lead to larger fractions of free molecule in the plasma which affords more rapid tumor uptake. Some APC chelates are cleared via the renal system, whereas iodinated analogs are eliminated through the hepatobiliary system. APC chelates also accumulate in tumors and clear from the blood much quicker than iodinated analog. Faster blood clearance is directly associated with lower bone marrow and off-target toxicity of therapeutic radiopharmaceuticals.
- the pharmacokinetic profile of the APC chelates can easily be manipulated by minor changes in the structure of the chelate (e.g. chelate charge).
- the choice of chelators is vast. Faster clearance from normal tissues improves imaging contrast and therapeutic windows, resulting in higher maximum tolerable doses.
- APC chelates possess different physico-chemical characteristics than iodinated analogs. They are much more water-soluble, and therefore do not need surfactants to render them suitable for intravenous injection. APC chelates are based on ionic binding of the metal to the chelate, whereas iodinated compounds form covalent bonds with their carrier molecules. In vivo de-iodination is quite common in alkyl iodides whereas chelates tend to be extremely stable in vivo.
- APC chelates In vivo biodistribution of APC chelates can be quite different depending on the metal ion so the metal and chelate also both contribute to the tumor targeting characteristics of the APC. Not all chelates target tumors. Tumor targeting depends on the cumulative properties of the APC carrier, the type of chelate (linear chelates undergo rapid renal elimination whereas macrocyclic chelates undergo hepatobiliary excretion), and the metal ion. Even slight changes in chelate structure result in significant variations on the in vivo properties. Simple changes in isotope can result in changes in tumor targeting larger than 50%.
- Radioactive APC-metal chelates are easily radiolabeled in nearly quantitative (>98%) yields under facile conditions, whereas radioiodination yields of iodinated analogs are much lower (typically about 50% for 1-131 and 60% for 1-124). Moreover, high specific activities can be achieved with chelates. Synthesis can be done using a radiolabeling kit in any nuclear pharmacy without the requirement of sophisticated ventilation equipment or training. Radioiodination must be done in a fume hood fitted with effluent monitoring equipment due to the volatility of radioactive iodine during the labeling reaction.
- Imaging agents don't necessarily make good therapy agents and vice versa.
- the three combination therapies showed substantial tumor growth inhibition, as compared to any of the single therapies (anti-CTLA4 or 90 Y-NM600 alone at three different dosages) or the PBS control.
- combination treatment with 50 or 100 ⁇ of 90 Y-NM600 with anti-CTLA4 had significantly (p ⁇ 0.05 by ANOVA) reduced tumor growth compared to PBS, 90 Y-NM600 alone, or anti-CTLA4 alone.
- the 25 ⁇ 90 Y-NM600 combination treatment group with anti-CTLA-4 had an intermediate growth delay response that showed a trend towards dose response.
- mice treated with 50 ⁇ of 90 Y-NM600 combined with anti-CTLA4 exhibited significantly greater aggregate survival than mice treated with TRT alone or PBS vehicle (p ⁇ 0.05).
- Example 15 In this follow-up to Example 15, we provide greatly expanded supporting data demonstrating the efficacy of the disclosed method combining systemically administering an immune checkpoint inhibitor and TRT performed by systemically administering the 90 Y-NM600 chelate used in previous examples. Efficacy is demonstrated in mouse melanoma, neuroblastoma and breast cancer models, as well as in multiple tumor melanoma models having disseminated "cold" tumors.
- MTRT 50 ⁇ (3 ⁇ 4, anti-CTLA4 (200 ⁇ g Days 4,7,10)
- MTRT and CTLA4 and PBS placebo control were our treatment groups.
- the effect of treatment on tumor immune cell populations was examined at day 1, 7, and 14 after radiation or saline placebo delivery by harvesting tumor tissue and freezing one portion for histology and saving another portion for quantitative PCR.
- the rest of the tumor sample was prepped for mRNA and RT-PCR analysis.
- Quantitative RT-PCR was used to evaluate changes in tumor cell expression of immune susceptibility markers (e.g. Fas, MHC-I, and PD- LI).
- mice with complete response to therapy were re-challenged with 2x10 6 B78 or lxl 0 6 Panc02 cells to the opposite flank 90 days after MTRT and then again at 120 days with Panc02 (only for B78) and B16 melanoma to test for tumor specific immune memory response.
- Quantitative PCR (qPCR) studies of gene expression also showed increased inflammatory gene expression including genes that are part of the stimulator of interferon gene pathway (STING).
- STING interferon gene pathway
- mice that had a complete response to therapy were in the combination therapy groups with 66%, 33, and 16% of the animals in the 50 uCi, 100, and 25 uCi MTRT dose groups. All mice that had a complete response at Day 60 after MTRT injection were challenged with B78 cells on the contralateral flank and there was a 100% rejection rate compared to naive controls, demonstrating that our treatment was able to generate an immune memory response. [00314] This study has since been replicated showing similar trends and survival across both studies showed a significantly improved overall survival in mice treated with combination MTRT (50, 100 uCi) and anti-CTLA4 compared to other groups by log rank test.
- mice with multiple bulky tumors we extended the study to demonstrate improved response rates in mice with multiple bulky tumors.
- mice were injected in one flank with 2 x 10 6 B78 melanoma tumor cells.
- mice were injected in the opposite flank with 5 x 10 5 B78 melanoma tumor cells.
- mice were injected intravenously with 2 x 10 5 B16 melanoma cells.
- mice were the exposed to various single or combination treatments: PBS control injection; MTRT, 50 ⁇ IV on Day 1 ; ICI, Anti-CTL A4/PD 1 on Days 4, 7 and 10; In Situ Vaccine (IS), 12 Gy local RT on Day 1 + intratumoral injection of anti-GD2 mAb and IL2 on Days 6-10.
- Tested single and combination treatments were PBS, MTRT, ICI, IS, MTRT + ICI, MTRT + IS, ICI + IS, and MTRT + IS + ICI. Beginning on Day 60, mice were monitored for tumor growth and animal survival, and tumor-free mice were rechallenged with B78 on Day 90.
- NM600 MTRT can enhance abscopal response in tumors when combined with checkpoint blockade.
- the NM600 MTRT radiotherapeutic delivery agent demonstrates the ability to improve response in "cold" tumors that normally do not respond to immune checkpoint blockade alone.
- a relatively low MTRT dose 50 ⁇ Ci (2.5 Gy tumor dose) is sufficient to achieve immunostimulatory effects to enhance ICI efficacy without systemic lymphodepletion.
- MTRT can be added to single site EBRT and checkpoint blockade to achieve greater tumor response and cure rates at both local and distant tumor sites. Our results show that MTRT has great potential to improve therapeutic efficacy of immunotherapy treatments in patients.
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BR112022010246A2 (en) * | 2019-11-27 | 2022-09-06 | Gi Innovation Inc | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF CANCER COMPRISING FUSION PROTEIN COMPRISING IL-2 PROTEIN AND CD80 PROTEIN AND IMMUNE CHECKPOINT INHIBITOR |
EP4096781A1 (en) | 2020-01-28 | 2022-12-07 | RefleXion Medical, Inc. | Joint optimization of radionuclide and external beam radiotherapy |
PE20221858A1 (en) * | 2020-03-26 | 2022-11-30 | Ramirez Fort Marigdalia Kaleth | TREATMENTS WITH ULTRAVIOLET RADIATION |
CN111840585B (en) * | 2020-07-20 | 2022-05-03 | 厦门大学 | Pharmaceutical composition for tumor immunotherapy |
WO2023141722A1 (en) * | 2022-01-28 | 2023-08-03 | Fusion Pharmaceuticals Inc. | Ntsr1-targeted radiopharmaceuticals and checkpoint inhibitor combination therapy |
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US7226577B2 (en) * | 2003-01-13 | 2007-06-05 | Bracco Imaging, S. P. A. | Gastrin releasing peptide compounds |
US8540968B2 (en) | 2004-03-02 | 2013-09-24 | Cellectar, Inc. | Phospholipid ether analogs as agents for detecting and locating cancer, and methods thereof |
WO2007013894A2 (en) * | 2004-12-20 | 2007-02-01 | Cellectar, Llc | Phospholipid ether analogs for detecting and treating cancer |
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EP4248999A3 (en) * | 2009-06-12 | 2023-11-15 | Cellectar, Inc. | Ether phospholipid compounds for treating cancer and imaging and detection of cancer stem cells |
JP2018518526A (en) * | 2015-06-25 | 2018-07-12 | アドバンスド アクセレレーター アプリケーションズ | Methods for treating neuroendocrine tumors overexpressing somatostatin receptors |
US20180214583A1 (en) * | 2015-08-12 | 2018-08-02 | Bayer Pharma Aktiengesellschaft | Pharmaceutical combination for the treatment of cancer |
EP3370779A1 (en) * | 2015-11-06 | 2018-09-12 | Wisconsin Alumni Research Foundation | Long-lived gadolinium based tumor targeted imaging and therapy agents |
JP7490361B2 (en) * | 2016-07-18 | 2024-05-27 | ウイスコンシン アラムナイ リサーチ ファウンデーシヨン | Radiohalogenated agents for in situ immunomodulatory cancer vaccination |
US11633506B2 (en) * | 2016-07-18 | 2023-04-25 | Wisconsin Alumni Research Foundation | Using targeted radiotherapy (TRT) to drive anti-tumor immune response to immunotherapies |
JP7438756B2 (en) * | 2016-07-25 | 2024-02-27 | ウイスコンシン アラムナイ リサーチ ファウンデーシヨン | Targeted radiotherapeutic chelates for in situ immunomodulatory cancer vaccination |
WO2018022125A1 (en) | 2016-07-25 | 2018-02-01 | Wisconsin Alumni Research Foundation | Radioactive phospholipid metal chelates for cancer imaging and therapy |
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AU2018366219A1 (en) | 2020-06-11 |
KR20200088374A (en) | 2020-07-22 |
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