Low dose haptenized tumor cell and tumor cell extract immunotherapy

Abstract

This invention relates to compositions comprising haptenized tumor cells and extracts thereof, methods for preparing the compositions, vaccines comprising such haptenized tumor cells, and methods for treating cancer with such vaccines. In a specific embodiment, melanoma cells are haptenized with a dinitrophenyl group, and used for treatment of melanoma patients having metastatic disease. Preferably, patients are given a first vaccine dose containing haptenized cells to “prime” the immune system. Subsequently, patients are injected with an immunomodulatory compound such as cyclophosphamide. In a preferred embodiment, an appropriate time period after the “priming” vaccine dose, additional vaccine doses containing a mixture of haptenized cells and an adjuvant are administered. The described treatment plan is more effective for eliciting favorable anti-tumor immune responses.

1 . A composition comprising a haptenized tumor cell or tumor cell extract comprising from about 2×10 5  to about 2.5×10 6  tumor cells or cell equivalents per dose, wherein the tumor cells or cell equivalents are conjugated to a hapten and rendered incapable of growth or multiplication in vivo.  
   
   
       2 . The composition of  claim 1 , wherein the hapten is selected from the group consisting of dinitrophenyl, trinitrophenyl, N-iodoacetyl-N′-(5-sulfonic 1-naphthyl) ethylene diamine, trinitrobenzenesulfonic acid, fluorescein isothiocyanate, arsenic acid benzene isothiocyanate, sulfanilic acid, arsanilic acid, dinitrobenzene-S-mustard and combinations thereof.  
   
   
       3 . The composition of  claim 2 , in which the hapten is dinitrophenyl.  
   
   
       4 . The composition of  claim 1 , wherein the tumor cell extract comprises tumor cell membrane components.  
   
   
       5 . The composition of  claim 1 , wherein the tumor cell extract comprises tumor cell polypeptides.  
   
   
       6 . The composition of  claim 1 , wherein the tumor cells or tumor cell extracts originate from a tumor selected from the group consisting of melanoma, ovarian cancer, colon cancer, breast cancer, rectal cancer, lung cancer, kidney cancer, prostate cancer, and leukemia.  
   
   
       7 . The composition of  claim 6 , wherein the tumor is melanoma.  
   
   
       8 . The composition of  claim 6 , wherein the tumor is ovarian cancer.  
   
   
       9 . The composition of  claim 1 , wherein the tumor cell or tumor cell extract has been rendered incapable of growth by irradiation.  
   
   
       10 . The composition of  claim 1 , free of any adjuvant.  
   
   
       11 . A method for inducing an anti-tumor response in a mammalian patient suffering from a tumor, which method comprises administering to the patient a composition comprising a haptenized tumor cell or tumor cell extract comprising from about 2×10 5  to about 2.5×10 6  tumor cells or cell equivalents per dose, wherein the tumor cells or cell equivalents are conjugated to a hapten, and rendered incapable of growth or multiplication in vivo.  
   
   
       12 . The method of  claim 10 , which further comprises administering a first dose of the composition without any adjuvant.  
   
   
       13 . The method of  claim 10 , wherein the composition is administered prior to a second composition comprising an adjuvant and a tumor cell or tumor cell extract, which second composition 
 a) is conjugated to a hapten, and    b) contains from about 2×10 5  to about 2.5×10 6  tumor cells or tumor cell equivalents.    
   
   
       14 . The method of  claim 13 , wherein the adjuvant is selected from the group consisting of Bacille Calmette-Guerin, Q-21, and detoxified endotoxin.  
   
   
       15 . The method of  claim 11 , wherein the composition is administered prior to the administration of cyclophosphamide.  
   
   
       16 . The method of  claim 14 , wherein the composition is administered four to seven days prior to the administration of cyclophosphamide.  
   
   
       17 . The method of  claim 10 , wherein the tumor cells or tumor cell extracts originate from a tumor selected from the group consisting of melanoma, ovarian cancer, colon cancer, breast cancer, rectal cancer, lung cancer, kidney cancer, prostate cancer, and leukemia.  
   
   
       18 . The method of  claim 10 , wherein the tumor cells or tumor cell extracts are autologous.  
   
   
       19 . The method of  claim 10 , wherein the tumor is melanoma.  
   
   
       20 . The method of  claim 10 , wherein the patient is a human.  
   
   
       21 . A method for inducing an anti-tumor response in a mammalian patient suffering from a tumor, which method comprises administering to the patient: 
 (a) on the first day of the treatment, a composition comprising autologous tumor cells or tumor cell extracts, which corresponds to from about 2×10 5  to about 2.5×10 6  tumor cells, free of any adjuvant;    (b) four to seven days after initiation of the treatment, an immunomodulatory agent that potentiates protective anti-tumor immunity or inhibits immune suppression, or both; and    (c) at least one additional composition comprising autologous tumor cells or tumor cell extracts.    
   
   
       22 . The method of  claim 21 , in which the immunomodulatory compound is cyclophosphamide.  
   
   
       23 . A method for inducing an anti-tumor response in a mammalian patient suffering from a tumor, which method comprises administering to the patient: 
 (a) on the first day of the treatment, a composition comprising a haptenized autologqus tumor cell or tumor cell extract which corresponds to from about 2×10 5  to 2.5×10 6  tumor cells free from any adjuvant;    (b) four to seven days after initiation of the treatment, cyclophosphamide; and    (c) at least one week after initiation of the treatment, a composition comprising an adjuvant and a haptenized autologous tumor cell or tumor cell extract which corresponds to from about 2×10 5  to about 1×10 7  tumor cells.    
   
   
       24 . The method in  claim 22 , in which the adjuvant is Bacille Calmette-Guerin.