Concurrent Chemotherapy and Immunotherapy

Abstract

The concurrent administration of chemotherapy and immunotherapy has been considered a contraindication because of the concern that the induced lymphopenia would ablate therapeutic efficacy of immunotherapy. Temozolomide has been shown to be an effective chemotherapeutic for patients with malignant gliomas and to deprive patients with glioblastoma (GBM) patients of this agent in order to treat with immunotherapy is controversial. Despite conventional dogma, we demonstrate that both chemotherapy and immunotherapy can be delivered concurrently without negating the effects of immunotherapy. In fact, the temozolomide induced lymphopenia may actually be synergistic with a peptide vaccine.

We claim: 
     
         1 . A method of treating a tumor expressing EGFRvIII in a subject, comprising the steps of:
 administering to the subject an amount of an EGFRvIII peptide effective to induce an IgG response to EGFRvIII peptide or to induce EGFRvIII peptide-specific γ-IFN producing CD8 +  T cells, after administering an amount of temozolomide or a pharmaceutically acceptable salt thereof effective to induce lymphopenia of CD8+ T cells; wherein the combined administration of the peptide and the temozolomide or pharmaceutically acceptable salt thereof increases immunotherapeutic efficacy.   
     
     
         2 . The method of  claim 1  wherein the EGFRvIII peptide is conjugated to keyhole limpet hemocyanin (KLH). 
     
     
         3 . The method of  claim 1  further comprising the step of:
 administering to the subject GM-CSF as an adjuvant in an effective amount concurrently with the EGFRvIII peptide. 
 
     
     
         4 . The method of  claim 1  wherein the EGFRvIII peptide has the sequence LEU-GLU-GLU-LYS-LYS-GLY-ASN-TYR-VAL-VAL-THR-ASP-HIS-CYS (SEQ ID NO: 3) and wherein KLH is conjugated to the CYS residue. 
     
     
         5 . The method of  claim 4  wherein the EGFRvIII peptide is conjugated to the KLH with a heterobifunctional cross-linker. 
     
     
         6 . The method of  claim 5  wherein the heterobifunctional cross-linker is sulfosuccinimidyl 6-[3′(2-pyridyldithio)-propionamido]hexanoate. 
     
     
         7 . The method of  claim 1  wherein a treatment effective amount of temozolomide is administered. 
     
     
         8 . The method of  claim 1  wherein the tumor is a malignant glioma. 
     
     
         9 . The method of  claim 1  wherein a treatment effective amount of a pharmaceutically acceptable salt of temozolomide is administered. 
     
     
         10 . A method of treating a tumor expressing EGFRvIII in a subject, comprising the steps of:
 administering to the subject an amount of an EGFRvIII peptide conjugated to KLH effective to induce an IgG response to EGFRvIII peptide or EGFRvIII peptide-specific γ-IFN producing CD8 +  T cells after administering to the subject an amount of temozolomide or a pharmaceutically acceptable salt thereof effective to induce lymphopenia of CD8 +  T cells; and   administering to the subject GM-CSF as an adjuvant in an effective amount concurrently with the EGFRvIII peptide; wherein the combined administration of the peptide and the temozolomide or the pharmaceutically acceptable salt increases immunotherapeutic efficacy.   
     
     
         11 . The method of  claim 10  wherein the tumor is a malignant glioma. 
     
     
         12 . The method of  claim 10  wherein a treatment effective amount of temozolomide is administered. 
     
     
         13 . The method of  claim 1  wherein the EGFRvIII peptide is administered after the CD8+ T cells begin to recover from nadir of the induced lymphopenia. 
     
     
         14 . The method of  claim 10  wherein the EGFRvIII peptide is administered after the CD8+ T cells begin to recover from nadir of the induced lymphopenia. 
     
     
         15 . The method of  claim 1  wherein the EGFRvIII peptide is administered after T REG  cells in the subject reach a peak and are declining in response to the temozolomide or the pharmaceutically acceptable salt. 
     
     
         16 . The method of  claim 10  wherein the EGFRvIII peptide is administered after T REG  cells in the subject reach a peak and are declining in response to the temozolomide or the pharmaceutically acceptable salt. 
     
     
         17 . The method of  claim 1  wherein the peptide and the temozolomide or salt thereof are administered repeatedly in a cycle. 
     
     
         18 . The method of  claim 10  wherein the peptide and the temozolomide or salt thereof are administered repeatedly in a cycle. 
     
     
         19 . The method of  claim 1  wherein the combined administration induces a DTH response in the subject. 
     
     
         20 . The method of  claim 10  wherein the combined administration induces a DTH response in the subject. 
     
     
         21 . The method of  claim 1  wherein EGFRvIII peptide-specific γ-IFN producing CD8 +  T cells are induced in the subject. 
     
     
         22 . The method of  claim 10  wherein EGFRvIII peptide-specific γ-IFN producing CD8 +  T cells are induced in the subject. 
     
     
         23 . The method of  claim 1  wherein an IgG response to EGFRvIII peptide is induced in the subject. 
     
     
         24 . The method of  claim 1  wherein an IgG response to EGFRvIII peptide is induced in the subject.