Methods for combining adoptive t cell therapy with oncolytic virus adjunct therapy

Abstract

The present invention relates to augmenting the effects of adoptive T cell therapy, such as TVAX Immunotherapy, using adjunct treatment with an oncolytic virus, such as a vaccinia virus, to treat various types of cancer or other proliferative disorders. Immunomodulatory compounds can be used to further augment to effects of the therapy.

We claim: 
     
         1 . A cancer immunotherapy method for treating cancer in a patient comprising:
 vaccinating the patient with a vaccine comprised of the patient's own malignancy and an immunologic adjuvant;   isolating primed T lymphocytes from lymphoid tissue, peripheral blood or cancer tissue of the patient;   stimulating the primed T lymphocytes to differentiate into effector T lymphocytes in vitro;   stimulating the effector T lymphocytes to proliferate in vitro;   administering an oncolytic virus to the patient; and   infusing the effector T lymphocytes back into the patient.   
     
     
         2 . The method of  claim 1 , further comprising administering a booster vaccination comprising a first oncolytic virus after the vaccination step and prior to the isolating primed T lymphocytes step. 
     
     
         3 . The method of  claim 1 , wherein the vaccinating step is preceded by administration of a first oncolytic virus within two weeks prior to the vaccinating step. 
     
     
         4 . The method of  claim 1 , wherein the oncolytic virus is selected from the group consisting of vaccinia virus, reovirus, measles virus, mumps virus, adenovirus and herpes virus, vesicular stomatitis virus, newcastle disease virus, parvovirus, poliovirus, coxsackie virus, sindbis virus, seneca valley virus, maraba virus and combinations thereof. 
     
     
         5 . The method of  claim 4 , wherein the oncolytic vaccinia virus is selected form the group consisting of Lister, Western Reserve (WR), Copenhagen (Cop), Bern, Paris, Tashkent, Tian Tan, Wyeth (DRYVX), IHD-J, IHD-W, Brighton, Ankara, CVA382, Modified Vaccinia Ankara (MVA), Dairen I, LC16m8, LC16M0, LIVP, ACAM2000, WR 65-16, Connaught, New York City Board of Health (NYCBH), EM-63 and NYVAC strain, and combinations thereof. 
     
     
         6 . The method of  claim 5 , wherein the oncolytic vaccinia virus is selected from the group consisting JX594 and derivatives thereof, WO-12 and derivatives thereof, the GL-ONC1 (i.e., GLV-1h68) and derivatives thereof, clonal strains of LIVP and Copenhagen, and combinations thereof. 
     
     
         7 . The method of  claim 1 , wherein the cancer is selected from the group consisting of breast cancer, brain and central nervous system cancer, kidney cancer, and ovarian cancer. 
     
     
         8 . The method of  claim 1 , further comprising after the infusing step, administering a second oncolytic virus to the patient. 
     
     
         9 . The method of  claim 1 , further comprising before the vaccinating step, administering a first oncolytic virus to the patient, and then removing the patient's own malignancy. 
     
     
         10 . The method of  claim 1 , further comprising before the vaccinating step, removing the patient's own malignancy and administering a first oncolytic virus to the patient, wherein administering the first oncolytic virus occurs simultaneously with or after the removing the patient's own malignancy. 
     
     
         11 . The method of  claim 1 , further comprising before the vaccinating step, removing the patient's own malignancy, combining the patient's own malignancy with a first oncolytic virus and using the combined virus/malignancy in the vaccinating step. 
     
     
         12 . The method of  claim 1 , wherein a second oncolytic virus is delivered by the effector T lymphocytes in the infusion step. 
     
     
         13 . The method of any of  claims 1 - 12 , further comprising administering an immunomodulatory compound. 
     
     
         14 . The method of  claim 13 , comprising administering 2 to 6 immunomodulatory compounds. 
     
     
         15 . The method of  claim 13 , wherein the immunomodulatory compound is infused into the patient with the effector T lymphocytes, administered to the patient after the infusing step, administered to the patient after the vaccinating step and prior to the isolating primed T lymphocytes step, and/or delivered to the primed T lymphocytes between the isolating step and the infusing step. 
     
     
         16 . The method of  claim 15 , wherein the immunomodulatory compound is delivered to the primed T lymphocytes during the differentiation step, the proliferation step, or both. 
     
     
         17 . The method of  claim 13 , wherein the immunomodulatory compound is selected from the group consisting of compounds that bind to or otherwise interfere with the function of immune-inhibitory signaling molecules, agonistic compounds that activate or augment the immunostimulatory signaling molecules, and combinations thereof. 
     
     
         18 . The method of  claim 17 , wherein the immunomodulatory compound activates or augments the immunostimulatory signaling molecule selected from the group consisting of TNF and TNFR superfamily molecules, B7 and CD28-related proteins, NK cell targets, soluble mediators, immune checkpoint ligands and receptors, toll-like receptor family molecules, phopshatidylserine, SIRPA-CD47, VEGF, neuropilin and combinations thereof. 
     
     
         19 . The method of  claim 18 , wherein the immunomodulatory compound is selected from the group consisting of Ipilimumab, Pembrolizumab, Nivolumab, Atezolizumab, and combinations thereof. 
     
     
         20 . The method of  claim 13 , wherein the immunomodulatory compound is selected from the group consisting of genetically engineered or otherwise modified antibodies, natural ligands, small molecules, and combinations thereof. 
     
     
         21 . The method of any of  claims 1 - 20 , wherein the oncolytic virus has been genetically engineered to include deletion of a gene encoded by the wild-type strain of the virus, wherein the genes encodes immune modifying gene product(s), metabolic gene product(s), or cell cycle controlling gene product(s). 
     
     
         22 . The method of any of  claims 1 - 20 , wherein the oncolytic virus has been genetically engineered to encode a gene product selected from the group consisting of an anti-cancer agent, an anti-angiogenic agent, an immunomodulatory molecule or an antigen (e.g., cancer (neo)antigens, cancer-associated antigens, tissue-specific antigens, bacterial antigens, viral antigens, yeast antigens, fungal antigens, protozoan antigens, parasite antigens and mitogens), a hormone, a growth factor, a cytokine, a chemokine, a costimulatory molecule, a ribozyme, a transporter protein, a single chain antibody (e.g., an anti-VEGF or anti-VEGFR, or anti-EGFR antibody), an antibody (agonistic or antagonistic) against immune modulating proteins, an antisense or ds RNA or other RNA product, a prodrug converting enzyme, an siRNA, a microRNA, a toxin, an anti-cancer oligopeptide, a mitosis inhibitor protein, an antimitotic oligopeptide, an anti-cancer polypeptide antibiotic, an angiogenesis inhibitor, a cancer suppressor, a cytotoxic protein, a cytostatic protein, an enzyme that modifies a substrate to produce a detectable product or signal, an enzyme detectable by antibodies, a protein that can bind a contrasting agent. 
     
     
         23 . A cancer immunotherapy method for treating cancer in a patient comprising:
 Isolating T lymphocytes from lymphoid tissue, peripheral blood or cancer tissue of the patient;   optionally genetically engineering the T lymphocytes;   stimulating the T lymphocytes to differentiate into effector lymphocytes in vitro;   stimulating the effector T lymphocytes to proliferate in vitro;   infusing the effector T lymphocytes back into the patient; and   one or more of:
 administering an oncolytic virus to the patient after stimulating the effector T lymphocytes and prior to the infusing step; 
 prior to the isolating step, administering the same or different oncolytic virus to the patient as a booster vaccine after vaccinating the patient with a vaccine comprised of the patient's own malignancy; 
 prior to the isolating step, administering the same or different oncolytic virus to the patient as a prior to vaccinating the patient with a vaccine comprised of the patient's own malignancy; 
 administering the same or different oncolytic virus to the patient after the infusing step; 
 prior to the isolating step, administering the same or different oncolytic virus to the patient and then removing the patient's own malignancy prior to vaccinating the patient with the vaccine comprised of the patient's own malignancy; 
 prior to the isolating step, removing the patient's own malignancy and then administering the same or different oncolytic virus to the patient prior to vaccinating the patient with the vaccine comprised of the patient's own malignancy; 
 prior to the isolating step, removing the patient's own malignancy, combining the malignancy with the same or different oncolytic virus, and using the combined virus/malignancy to vaccinate the patient; and 
 delivering the same or different oncolytic virus by the effector T lymphocytes in the infusion step. 
   
     
     
         24 . The method of  claim 23 , wherein each oncolytic virus is independently selected from the group consisting of vaccinia virus, reovirus, measles virus, mumps virus, adenovirus and herpes virus, vesicular stomatitis virus, newcastle disease virus, parvovirus, poliovirus, coxsackie virus, sindbis virus, seneca valley virus, maraba virus and combinations thereof. 
     
     
         25 . The method of  claim 23 , wherein the cancer is selected from the group consisting of breast cancer, brain and central nervous system cancer, kidney cancer, and ovarian cancer. 
     
     
         26 . The method of  claim 23 , further comprising administering an immunomodulatory compound. 
     
     
         27 . The method of  claim 26 , wherein the immunomodulatory compound is selected from the group consisting of compounds that bind to or otherwise interfere with the function of immune-inhibitory signaling molecules, agonistic compounds that activate or augment the immunostimulatory signaling molecules, and combinations thereof. 
     
     
         28 . A cancer immunotherapy method for treating cancer in a patient comprising:
 vaccinating the patient with a first oncolytic virus;   isolating primed T lymphocytes from the peripheral blood, lymphoid tissue or cancer tissue of the patient;   stimulating the primed T lymphocytes to differentiate into effector lymphocytes in vitro;   stimulating the effector T lymphocytes to proliferate in vitro; and   infusing the effector T lymphocytes back into the patient.   
     
     
         29 . The method of  claim 28 , wherein the cancer is inoperable. 
     
     
         30 . The method of  claim 28 , further comprising one or more of:
 administering a second oncolytic virus to the patient after stimulating the T lymphocytes and prior to the infusing step;   administering the same or different second oncolytic virus to the patient as a booster vaccine after the vaccinating step;   administering a the patient's own malignancy and an immunologic adjuvant to the patient as a booster vaccine after the vaccinating step;   administering the same or different second oncolytic virus to the patient after the infusing step;   prior to the vaccinating step, administering the same or different second oncolytic virus to the patient and then removing the patient's own malignancy;   prior to the vaccinating step, removing the patient's own malignancy and then administering the same or different second oncolytic virus to patient prior;   prior to the vaccinating step, removing the patient's own malignancy, combining the malignancy with the same or different second oncolytic virus, and using the combined virus/malignancy as an additional vaccinating step; and   delivering the same or different oncolytic virus by the effector T lymphocytes in the infusion step.   
     
     
         31 . The method of  claim 30 , wherein each oncolytic virus is independently selected from the group consisting of vaccinia virus, reovirus, measles virus, mumps virus, adenovirus and herpes virus, vesicular stomatitis virus, newcastle disease virus, parvovirus, poliovirus, coxsackie virus, sindbis virus, seneca valley virus, maraba virus and combinations thereof. 
     
     
         32 . The method of  claim 30 , wherein the cancer is selected from the group consisting of breast cancer, brain and central nervous system cancer, kidney cancer, and ovarian cancer. 
     
     
         33 . The method of  claim 30 , further comprising administering an immunomodulatory compound.