ECHO-7 ONCOLYTIC VIRUS FOR USE IN THE TREARMENT OF UVEAL MELANOMA

Abstract

Provided herein is the use of an ECHO-7 class oncolytic virus for the treatment of uveal melanoma and compositions comprising the ECHO-7 virus and pharmaceutically acceptable carrier for the treatment of uveal melanoma.

Claims

1. Use of ECHO-7 type virus comprising composition in the treatment of uveal melanoma, selected from primary and metastatic uveal melanoma.

2. The use according to claim 1, wherein the uveal melanoma is treated by parenteral administration of the said ECHO-7 type virus comprising composition.

3. The use according to claim 1, wherein the uveal melanoma is treated by intraocular administration of the said ECHO-7 type virus comprising composition.

4. The use according to claim 2, wherein the uveal melanoma is treated by retrobular administration of the said ECHO-7 type virus comprising composition.

5. The use according to claim 3, wherein said ECHO-7 type virus comprising composition is administered by intravitreal injection.

6. The use according to claim 2, wherein the ECHO-7 type virus comprising composition is administered topically.

7. The use according to claim 1, wherein the ECHO-7 type virus is in an amount in the range of 210.sup.6 to 210.sup.8 TCID.sub.50/ml per single dose.

8. ECHO-7 type virus for the treatment of uveal melanoma, which is selected from primary and metastatic uveal melanoma.

9. A pharmaceutical composition for the treatment of uveal melanoma comprising the ECHO-7 type virus of claim 8.

10. A pharmaceutical composition according to claim 9, comprising an amount of ECHO-7 type virus is in the range of 210.sup.6 to 210.sup.8 TCID.sub.50/ml per single dose.

11. A pharmaceutical composition according to claim 9 for parenteral administration.

12. A pharmaceutical composition according to claim 11 for intraocular administration.

13. A pharmaceutical composition according to claim 11 for retro-bulbar administration.

14. A pharmaceutical composition according to claim 11 for administration by intravitreal injection.

15. A pharmaceutical composition according to claim 9 for topical administration.

16. A pharmaceutical composition according to claim 10 for parenteral administration.

17. A pharmaceutical composition according to claim 16 for intraocular administration.

18. A pharmaceutical composition according to claim 16 for retro-bulbar administration.

19. A pharmaceutical composition according to claim 16 for administration by intravitreal injection.

20. A pharmaceutical composition according to claim 10 for topical administration.

Description

FIGURES

[0039] FIG. 1. Effect of ECHO-7 type virus on viable cell count 0 to 96 h. Statistical difference in cell viability between ECHO-7 type virus treated and control was observed from the following time-points.

[0040] Statistically significantly difference vs. control P<0.05 (*), not statistically different (n.s.). Data are expressed as meansS.E.M.

[0041] Control (.circle-solid.), ECHO-7 type virus (1%) (.square-solid.) and ECHO-7 type virus (10%) (.box-tangle-solidup.).

[0042] FIG. 1 A. Effect on 92-1 cells: ECHO-7 type virus (1%) at 44 h (P=0.0459) and ECHO-7 type virus (10%) at 14 h (P=0.0036).

[0043] FIG. 1 B. Effect on Mel202 cells: ECHO-7 type virus (1%) at 23 h (P=0.0260) and ECHO-7 type virus (10%) at 11 h (P=0.0083).

[0044] FIG. 1 C. Effect on MP-41 cells: ECHO-7 type virus (1%) at 27 h (P=0.0362) and ECHO-7 type virus (10%) at 23 h (P=0.0241).

[0045] Treatment of Patients with Uveal Melanoma

[0046] The present invention includes methods for the treatment and prevention of uveal melanoma of the eye and metastases comprised of the following steps: selecting a pharmaceutical formulation comprising ECHO-7 type virus and an appropriate carrier; administration by injection or infusion or by applying topically of said drug directly into the eye or subcutaneously, intradermally, intramuscularly, intra-peritoneally, intranasally or intravenously at an effective amount, at an effective number of occasions, and for a sufficient period of time to invade cancer cells with ECHO-7.

[0047] The present invention includes further ECHO-7 type virus for use in the treatment and prevention of uveal melanoma of the eye and metastases thereof. As used herein, the term carrier or pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, and the like and combinations thereof, as would be known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 22.sup.nd Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with Echovirus, its use for therapy in pharmaceutical compositions is contemplated.

[0048] Subcutaneous, intramuscular, intranasal, intradermal, intraperitoneal or intravenous injections or locally administering directly into the eye of appropriate formulation to achieve the desired therapeutic objective is used to deliver a sufficient quantity or effective amount of ECHO-7 type virus to the target space. Preferably, according to instant invention the pharmaceutical composition comprising ECHO-7 type virus is administered parenteral, retro-bulbar or by intravitreal injection.

[0049] As used herein, locally administering refers to the direct administration of a drug to a site (for example to a target space of the eye), as opposed to drug delivery to that site by a systemic route or intravascular route or eye drops or gels. As used herein, physical carrier refers to carrier wherein the drug is absorbed on the surface of the physical carrier. Examples of pharmaceutically acceptable physical carriers include but are not limited to, ophthalmological grade sponges, gauze, cellulose sponges and gels. Biocompatible physical carriers that can be used in the eye are well known to one skilled in the art. /Rautio, J. et al., Nat Rev Drug Discov., 7(3): 255-70 (March 2008); Yasukawa, T. et al., Adv Drug Deliv Rev, 57(14): 2033-46 (Dec. 13, 2005); and Bourges, J. L. et al., Adv Drug Deliv Rev, 58(11):1182-202 (Nov. 15, 2006)/.

[0050] As used herein, pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0051] The term pharmaceutical composition is defined herein to refer to a mixture or solution, suspensions or emulsions containing ECHO-7 type virus to be administered to a warm-blooded animal, e.g., a mammal or human, in order to prevent or treat uveal melanoma affecting the warm-blooded animal inclusive human.

[0052] Methods of injection into the eye are well known to one skilled in the art and is done with a needle or catheter inserted into the vitreal space. Micro-infusion techniques, micro-needles and micro-catheters can also be used and are well known to one skilled in the art.

[0053] The ECHO-7 type virus can be formulated in a pharmaceutical composition comprising an effective amount of a drug, and a pharmaceutically acceptable carrier both for parenteral or locally administration.

[0054] The carriers are pharmaceutically acceptable in that they are not deleterious to the recipient thereof in an amount used in the medicament. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the methods of this invention include, but are not limited to buffer substances, such as phosphates, glycine, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0055] The formulation can be a solution, suspension, emulsion, gel, polymeric paste. The drugs can be administered in combination with commonly employed pharmacological excipients, which include but are not limited to, saline, aqueous buffers, cyclodextrins, sodium hyaluronate, and stabilizers that are well known to one skilled in the art. ECHO-7 type virus can be dissolved in sterile saline or water or a buffered salt solution. In a preferred embodiment for intravitreal injections the virus is dissolved in an ophthalmological formulation of 1% sodium hyaluronate. In a preferred embodiment no organic solvent is employed in the formulation, rather the drug is formulated as a dry powder, to which is added an aqueous solution such as saline or ophthalmological grade of 1% sodium hyaluronate prior to administration.

[0056] For intramuscular or intravenous administration ECHO-7 type virus is formulated as a solution for injection or a dry powder, to which is added distilled water or an aqueous solution of saline.

[0057] The concentration, volume and total dose of the drug is dependent upon the clinical condition to be treated and the desired pharmacological effect. For intravitreal injections the injection volume will typically be in the range of 1 l to 100 l. In a preferred embodiment the injection volume is 50 l for intravitreal injections. Techniques for the determination of clinical drug doses and concentrations are well known to one skilled in the art. The drug may be administered by one or more local injections or by catheters placed within the eye and connected to micro-infusion pumps. Suitable catheters and micro-infusion pumps, and injection techniques are well known to one skilled in the art.

[0058] For intramuscular or intravenous administration ECHO-7 type virus usually is administered at a dose of 2 ml of 10.sup.6 to 10.sup.8 TCID.sub.50/ml.

[0059] The treatment may include but is not limited to injections of ECHO-7 for 3 consecutive days every 4 weeks for an initial 3-month period. Thereafter, the treatment has to be continued monthly during the first year, every 6 weeks during the first half of the second year, every 2 months during the second half of the second year and every 3 months during the third year. The treatment can be varied in accordance to clinical response and overall condition of the patient.

Example 2. Preliminary Results of Treatment of Uveal Melanoma Patients by Intramuscular Administration of ECHO-7

[0060] In a retrospective study ECHO-7 type virus containing composition at a dose of 2 ml of 10.sup.6 to 10.sup.8 TCID.sub.50/ml was applied intramuscularly to six patients (4 women and 2 men, age 31 to 61 year) with uveal melanoma after previous local irradiation therapy. Injections of ECHO-7 type virus were performed intramuscularly for three consecutive days every 4 weeks for an initial 3-month period. Thereafter, the treatment has been continued monthly during the first year, every 6 weeks during the first half of the second year, every 2 months during the second half of the second year and every 3 months during the third year.

[0061] During the treatment period all patients were investigated for primary melanoma progression and for development of metastasis. In four of six patients (67%), no sign of disease progression was noted. No side effect was reported for patients treated with ECHO-7 type virus. Two patients of six (33%) developed metastasis in the liver. For one of them disease became lethal during the second year after beginning ECHO-7 type virus treatment.

Example 3

[0062] Another group of five patients with uveal melanoma (1 man and 4 women, age 49 to 61 years) previously irradiated locally, received ECHO-7 type virus for one year by intramuscular injection (following administration route and dosages as described above). During the following two years these patients received ECHO-7 type virus locally. During all period of the treatment, patients were investigated for primary melanoma progression and for development metastasis. Progression free survival up to end of 36-month period of treatment was noted for five out of six patients (83%). One of patients suffered from development of metastasis in liver and died after 29 months.

Example 4. Long-Term ECHO-7 Treatment of a Uveal Melanoma Patient

[0063] Uveal melanoma was diagnosed in a 56-year old woman in 2007. After irradiation remission of uveal melanoma was noted. In 2010 progression of disease locally was noted. Locally irradiation of the eye was performed, but progression of malignant process was not stopped. Therefore, enucleation of the eye along with the optic nerve were performed in October 2016. After surgery administration of ECHO-7 type virus intramuscularly was started following the protocol, described for first group of patients in Example 1. After three years of treatment, progression of disease was not observed. Treatment did not cause any side effect.

[0064] In summary: The experimental evidence shows that ECHO-7 type virus is an effective and very safe drug for the treatment of uveal melanoma patients. ECHO-7 type virus is appropriate for the preparation of a pharmaceutical composition to be administered locally as well as parenterally and can be used for the prophylaxis and treatment of primary tumour and metastasis of uveal melanoma.