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    • 专利摘要:
    This document provides methods and materials for generating CD8
    公开号:AU2013221309A1
    申请号:U2013221309
    申请日:2013-02-15
    公开日:2014-09-04
    发明作者:Andrea M. HENLE；Keith L. Knutson
    申请人:Mayo Foundation for Medical Education and Research；
    IPC主号:C07K7-06
    专利说明:
    WO 2013/123424 PCT/US2013/026484 METHODS AND MATERIALS FOR GENERATING CD8* T CELLS HAVING THE ABILITY TO RECOGNIZE CANCER CELLS EXPRESSING A HER2/NEU POLYPEPTIDE 5 CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No. 61/600,480, filed February 17, 2012. The disclosure of the prior application is considered part of (and is incorporated by reference in) the disclosure of this application. 10 BACKGROUND 1. Technical Field This document relates to methods and materials for generating CD8' T cells having the ability to recognize cancer cells expressing a HER2/neu polypeptide. For example, this document relates to methods and materials for using a polypeptide 15 consisting of an SLAFLPESFD amino acid sequence in vivo or in vitro to generate CD8' T cells having the ability to recognize cancer cells expressing a HER2/neu polypeptide. 2. Background Information Cancer vaccines have the ability to stimulate or restore the immune system so that 20 it can fight cancer. In some cases, cancer vaccines can be designed to treat an existing cancer by strengthening the patient's defenses against the cancer. SUMMARY This document provides methods and materials for generating CD8' T cells 25 having the ability to recognize cancer cells expressing a HER2/neu polypeptide. For example, this document provides methods and materials for using a polypeptide consisting of an SLAFLPESFD amino acid sequence (SEQ ID NO:1) in vivo or in vitro to generate CD8' T cells having the ability to recognize and lyse cancer cells expressing a HER2/neu polypeptide. A polypeptide consisting of an SLAFLPESFD amino acid 30 sequence can be referred to as the SLAFLPESFD polypeptide, the p373-382 polypeptide, or a polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 1. As 1 WO 2013/123424 PCT/US2013/026484 described herein, the SLAFLPESFD polypeptide or a vaccine composition containing the SLAFLPESFD polypeptide can be administered to a cancer patient having cancer cells that express a HER2/neu polypeptide under conditions wherein the patient produces CD8' T cells having the ability to recognize and lyse those cancer cells. In some cases, 5 such CD8' T cells can be referred to as CD8' T cells generated using the SLAFLPESFD polypeptide. Having the ability to generate CD8' T cells with the ability to recognize and lyse cancer cells that express a HER2/neu polypeptide can allow clinicians to provide cancer patients with additional effective treatment options. For example, the vaccines provided 10 herein can be used alone or in combination with other cancer treatment options to provide cancer patients with an effective population of CD8' T cells designed to kill cancer cells that express a HER2/neu polypeptide. In general, one aspect of this document features a polypeptide (e.g., a purified polypeptide), wherein the sequence of the polypeptide consists of the amino acid 15 sequence set forth in SEQ ID NO:1. In some case, the polypeptide can include an N and/or C terminal modification. In another aspect, this document features a vaccine composition comprising, or consisting essentially of, a polypeptide (e.g., a purified polypeptide), wherein the sequence of the polypeptide consists of the amino acid sequence set forth in SEQ ID 20 NO: 1. In some case, the polypeptide can include an N and/or C terminal modification. The composition can comprise an adjuvant. The adjuvant can be an oil and water mixture. The adjuvant can be Montanide ISA-51. The composition can comprise IL-2, IL-12, GM-CSF, or rintatolimod. In another aspect, this document features a method for increasing the number of 25 CD8+ T cells having the ability to kill cancer cells expressing a HER2/neu polypeptide. The method comprises, or consists essentially of, contacting a population of CD8' T cells with a polypeptide (e.g., a purified polypeptide), wherein the sequence of the polypeptide consists of the amino acid sequence set forth in SEQ ID NO: 1. The contacting step can occur in an ex vivo manner. The contacting step can occur in an in vivo manner. 30 In another aspect, this document features a method for increasing, within a human, the number of CD8' T cells having the ability to kill cancer cells expressing a 2 WO 2013/123424 PCT/US2013/026484 HER2/neu polypeptide. The method comprises, or consists essentially of, administering a vaccine composition to the human, wherein the composition comprises, or consists essentially of, a polypeptide (e.g., a purified polypeptide), wherein the sequence of the polypeptide consists of the amino acid sequence set forth in SEQ ID NO: 1. In some case, 5 the polypeptide can include an N and/or C terminal modification. The human can contain cancer cells expressing the HER2/neu polypeptide. The composition can comprise an adjuvant. The adjuvant can be an oil and water mixture. The adjuvant can be Montanide ISA-51. The composition can comprise IL-2, IL-12, GM-CSF, or rintatolimod. The method can comprise administering IL-2, IL-12, GM-CSF, rintatolimod, or a 10 combination thereof to the human. The method can further comprise administering trastuzumab to the human. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those 15 described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to 20 be limiting. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. DESCRIPTION OF DRAWINGS 25 Figure 1A shows example total ion chromatograms identifying polypeptides derived from HER-2/neu 19-mer polypeptide (FAGCKKIFGSLAFLPESFD) by proteasomal or immunoproteasomal catalysis. Figure 1 B shows example extracted ion chromatograms from the reactions described in Figure 1A examining processing of HER-2/neu p369-377 from the 19-mer 30 polypeptide. 3 WO 2013/123424 PCT/US2013/026484 Figure 1 C shows example extracted ion chromatograms demonstrating that p373 382 (SLAFLPESFD) is processed from a HER-2/neu-derived 23-mer (QEFAGCKKIFGSLAFLPESFDGD) by proteasomal or immunoproteasomal catalysis. Figure 2A shows HER-2/neu polypeptide p373-382 binding to TAP deficient T2 5 cells. Figure 2B shows dose dependent saturable binding of HER-2/neu polypeptide p373-382 to T2 cells. Figure 2C shows relative binding affinities of HER-2/neu polypeptide p373-382 and p369-377 compared to high affinity influenza-derived HLA-A2 binding polypeptide, 10 GILGFVFTL (p58-66). Figure 3A shows IFN-y ELIspot analysis showing that CD8 T cells generated against HER-2/neu polypeptide p373-382 respond to autologous cells loaded with either p373-382 or p369-377. Figure 3B shows IFN-y ELIspot analysis demonstrating that CD8 T cells 15 generated against HER-2/neu polypeptide p373-382 respond to HER-2/neu-expressing tumor cells with release of IFN-y. Figure 3C shows cytotoxic T cell analysis demonstrating that CD8 T cells generated against HER-2/neu polypeptide p373-382 lyse HER-2/neu-expressing tumor cells. 20 Figures 4A-B shows, using IFN-y ELIspot analysis, that the IFN-y response of CD8 T cells generated against HER-2/neu polypeptide p373-382 is blocked by MHC class I blocking antibodies (Figure 4A: anti-HLA-A2; and Figure 4B: anti-HLA-ABC). Figures 4C-D shows, using cytotoxic T cell assays, that the lysis response of CD8 T cells generated against HER-2/neu polypeptide p373-382 is blocked by MHC class I 25 blocking antibodies (Figure 4C: anti-HLA-A2; and Figure 4D: anti-HLA-ABC). DETAILED DESCRIPTION This document provides methods and materials for generating CD8' T cells having the ability to recognize cancer cells expressing a HER2/neu polypeptide. For 30 example, this document provides methods and materials for using a polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 1 in vivo or in vitro to 4 WO 2013/123424 PCT/US2013/026484 generate CD8' T cells having the ability to recognize and lyse cancer cells expressing a HER2/neu polypeptide. In some cases, this document provides the SLAFLPESFD polypeptide and vaccine compositions containing the SLAFLPESFD polypeptide as well as methods for using the SLAFLPESFD polypeptide or vaccine compositions containing 5 the SLAFLPESFD polypeptide to generate CD8' T cells having the ability to recognize cancer cells expressing a HER2/neu polypeptide. In some cases, a polypeptide provided herein (e.g., a polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 1) can be used in combination with dendritic cells to treat cancer. For example, dendritic cells contacted with the 10 SLAFLPESFD polypeptide can be used to treat cancer. The SLAFLPESFD polypeptide provided herein can be substantially pure. The term "substantially pure" with respect to a polypeptide refers to a polypeptide that has been separated from cellular components with which it is naturally accompanied. For example, a synthetically generated polypeptide can be a substantially pure polypeptide. 15 Typically, a polypeptide provided herein is substantially pure when it is at least 60 percent (e.g., 65, 70, 75, 80, 90, 95, or 99 percent), by weight, free from proteins and naturally-occurring organic molecules with which it is naturally associated. In general, a substantially pure polypeptide will yield a single major band on a non-reducing polyacrylamide gel. 20 The SLAFLPESFD polypeptide provided herein can be prepared in a wide variety of ways. Because of its relatively short size, the SLAFLPESFD polypeptide can be synthesized in solution or on a solid automatic synthesizer in accordance with known protocols. See, for example, Stewart and Young, Solid Phase Polypeptide Synthesis, 2d. ed., Pierce Chemical Co. (1984); Tam et al., J. Am. Chem. Soc., 105:6442 (1983); 25 Merrifield, The Polypeptides, Gross and Meienhofer, ed., academic Press, New York, pp. 1-284 (1979). In some cases, a polypeptide provided herein (e.g., a SLAFLPESFD polypeptide) can be synthesized with either an amide (e.g., NH 2 ) or free acid (e.g., COOH) C terminus, both of which can have the ability to bind HLA-A2. In some cases, recombinant DNA technology can be used wherein a nucleic acid 30 sequence that encodes a SLAFLPESFD polypeptide provided herein is inserted into an expression vector, introduced (e.g., by transformation or transfection) into an appropriate 5 WO 2013/123424 PCT/US2013/026484 host cell, and cultivated under conditions suitable for expression. These procedures are generally known in the art, as described generally in Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, New York (1982), and Ausubel et al., (ed.) Current Protocols in Molecular Biology, John Wiley and Sons, 5 Inc., New York (1987), and U.S. Patent Nos. 4,237,224; 4,273,875; 4,431,739; 4,363,877; and 4,428,941, for example. This document also provides polypeptides (e.g., substantially pure polypeptides) consisting of one of the amino acid sequences set forth in Table 1. Such polypeptides can be made and used in the same manner described herein for the SLAFLPESFD 10 polypeptide. In some cases, the polypeptides provided herein can be incubated with a population of CD8' T cells to generate an activated pool of CD8' T cells that have the ability to recognize p373-382 or a HER2/neu polypeptide. For example, one or more of the polypeptides provided herein (e.g., the SLAFLPESFD polypeptide) can be used in an 15 ex vivo manner to created antigen-specific CD8' T cells that can be used to treat cancers. In some cases, the polypeptides provided herein can be used to generate a pool of activated HER2/neu polypeptide-specific CD8' T cells that can be used alone, or in combination with monoclonal antibody therapy, CTL therapy, or both monoclonal antibody therapy and CTL therapy, to treat cancer. For example, an anti-HER-2/neu 20 monoclonal antibody therapy can be combined with infusion of CD8' T cells generated using p373-382 polypeptides to treat cancer (e.g., breast cancer). In some cases, a Herceptin (trastuzumab) therapy can be combined with infusion of CD8' T cells generated using p373-382 polypeptides to treat cancer (e.g., breast cancer). This document also provides vaccine compositions that contain an 25 immunogenically effective amount of one or more of the polypeptides provided herein. A vaccine composition provided herein can be used both as a prevantative or therapeutic vaccine. The vaccine compositions provided herein can be administered and formulated using any appropriate techniques including, without limitation, those techniques described elsewhere (see, e.g., [0132] - [0173] of U.S. Patent Application Publication 30 No. 2010-0310640). 6 WO 2013/123424 PCT/US2013/026484 In some cases, a vaccine composition provided herein can include GM-CSF (e.g., sargramostim), rintatolimod (e.g., Ampligen*), IL-2, IL-12, an adjuvant, or a combination thereof. For example, a vaccine composition provided herein can include GM-CSF and an adjuvant. Examples of adjuvants include, without limitation, CpG 5 oligonucleotides, monophosphoryl lipid A, and Montanide ISA-5 1. In some cases, the adjuvant can be an oil and water mixture such as Montanide ISA-5 1. In some cases, a vaccine composition provided herein can include a combination of polypeptides. For example, a vaccine composition provided herein can include the SLAFLPESFD polypeptide and/or one or more of the other polypeptides set forth in 10 Table 1 in combination with one or more polypeptides set forth in U.S. Patent Application Publication No. 2010-0310640, the Karyampudi et al. reference (Clin. Cancer Res., 16(3):825-34 (2010)), the Holmes et al. reference (J. Clin. Oncol., 26(20):3426-33 (2008)), the Gritzapis et al. reference (Vaccine, 28(1):162-70 (2009)), the Perez et al. reference (Cancer Immunol. Immunother., 50(11):615-24 (2002)), the 15 Knutson et al. reference (J. Clin. Invest., 107(4):477-84 (2001)), or the Salazar et al. reference (Clin. Cancer Res., 9(15):5559-65 (2003)). Any appropriate method can be used to administer a vaccine composition provided herein to a mammal (e.g., a human). For example, a vaccine composition or polypeptide provided herein can be administered alone or in combination with other 20 polypeptides in doses ranging from 100 to 10,000 micrograms given by intradermal or subcutaneous routes monthly for a total of four to twelve months (e.g., 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). The methods and materials provided herein can be used to treat any type of cancer that expresses a HER2/neu polypeptide. For example, the methods and materials 25 provided herein can be used to treat breast cancer, ovarian cancer, colon cancer, esophageal cancer, or lung cancer. The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims. 30 7 WO 2013/123424 PCT/US2013/026484 EXAMPLES Example 1 - Identification of a potent class I MHC molecule epitope of a HER2/neu polypeptide HER-2/neu is a polypeptide that is overexpressed in a wide variety of cancers and 5 is a therapeutic target, particularly in breast cancer. For example, NeuVax is a previously developed vaccine that includes the HER-2/neu-derived polypeptide p369-377 (amino acid sequence: KIFGSLAFL (SEQ ID NO:2), also called E75) derived from the extracellular domain of HER-2/neu and mixed with GM-CSF. This vaccine aims to prime the immune response against E75 so that T cells are generated that can recognize 10 and kill the patient's cancer cells, which are presumably displaying the same peptides on their cell surface in association with MHC class I molecules. The following was performed to determine if E75 is processed from HER-2/neu or HER-2/neu fragments by multi-subunit enzymes referred to as the proteasome and immunoproteasome, which are required for loading of polypeptide onto MHC class I 15 molecules. To determine this, the 19-mer polypeptide, FAGCKKIFGSLAFLPESFD (SEQ ID NO:3), was synthesized. This polypeptide matches HER-2/neu amino acids 364-3 82, and it fully contains E75 (underlined). The 19-mer was then cleaved using purified 20S proteasome and immunoproteasome. Although E75 is reported to be cleaved as determined by proteasome algorithms, the in vitro data presented herein did 20 not reveal processing of this polypeptide from longer HER-2/neu polypeptides (Figures 1A and IB). However, the 19-mer polypeptide was consistently found to be processed into several other shorter polypeptides (Figure 1A and Table 1). None of these shorter polypeptides scored as highly as E75 for binding to HLA-A2 using the mathematical algorithms (Table 1). 8 WO 2013/123424 PCT/US2013/026484 -cc 44707 -c RC 0I -c =- ocC 9 WO 2013/123424 PCT/US2013/026484 CA1 CA C6 p 01 WO 2013/123424 PCT/US2013/026484 One of the observed processed polypeptides (p373-382) represented the end terminal ten amino acids of the 19-mer. To determine if this polypeptide could be processed from larger peptides, a 23-mer containing p373-382 was synthesized and 5 treated with the proteasomes. As shown in Figure IC, p373-382 was indeed released from the 23-mer. Many of the polypeptides that were processed in the assay were synthesized and tested for binding to the class I MHC molecule, HLA-A2, using the standard T2 HLA-A2 stabilization assay. HLA-A2 is an MHC class I molecule that is prevalent in 10 approximately 30-40% of the Caucasian population. It is often used as a target in vaccine trials since it has the potential to benefit a large number of breast cancer patients. One of the synthesized polypeptides, p373-382 (SLAFLPESFD), was able to strongly bind the HLA-A2 molecule, at levels comparable to the positive control, a polypeptide from the influenza virus (FLU) (Figure 2). Surprisingly, even low levels of p373-382 bound, 15 compared to p369-377, which required higher concentrations (Figure 2). Taken together, these results demonstrate that the HER-2/neu polypeptide p373 382 is processed from longer HER-2/neu polypeptides and binds HLA-A2. An ELIspot was performed to determine if the p373-382 epitope is naturally processed by the cellular machinery in cancer cells and to determine if it has the potential 20 of being bound to HLA-A2 on the surface of cancer cells, where it can serve as a target for primed and activated immune cells. If specific immune cells can recognize the p373 382:HLA-class I complex on cancer cells, then they can kill the cancer cells and prevent the cancer from progressing in patients. Since it was shown that the p373-382 polypeptide was processed in vitro by cellular machinery and was capable of binding 25 strongly to HLA-A2 molecules, an ELIspot was performed to determine whether CD8' T cells generated using the p373-382 polypeptide can be generated and if these T cells are able to recognize HER-2/neu* breast cancer cells. Figure 3A reveals that that CD8' T cell lines were generated using the pFLU polypeptide (control), p369-377, and p373-382. The control FLU T cells only recognized 30 target cells pulsed with FLU polypeptide, as expected. HER-2/neu p369-377 polypeptide-generated T cells recognized target cells pulsed with p369-377 polypeptide 11 WO 2013/123424 PCT/US2013/026484 and target cells pulsed with p373-382. p373-382-generated T cells recognized target cells pulsed with either the p373-382 polypeptide or the p369-377 polypeptide, indicating that there is cross-reactivity between the two polypeptides which could be due to the fact that they share five amino acids. 5 Next, the generated T cell lines were assessed in an in vitro ELISPOT assay to determine whether they could recognize a panel of breast cancer cell lines that express varying levels of HER-2/neu at their surface. In all cases, the p373-382-generated CD8' T cells were able to recognize the breast cancer cells at much higher levels compared to the p369-377-generated CD8' T cells and the control FLU CD8' T cells (Figure 3B). 10 BT20 cells express HER-2/neu, but do not express HLA-A2 and thus served as a negative control. These results indicate that breast cancer cells express p373-382 on their surface in the context of HLA-A2 and that CD8' T cells generated using p373-382 have the ability to recognize these cancer cells. Another in vitro assay was performed to measure lysis of the breast cancer cells 15 by the T cells. Again, the CD8' T cells generated using the p373-382 polypeptide recognized and lysed all tested breast cancer cell lines at much higher levels compared to the CD8' T cells generated using the p369-377 polypeptide (Figure 3C). In this assay, BT20 cells were a negative control as well as the FLO cells, which express HLA-A2, but do not express HER-2/neu. 20 Lastly, in order to confirm that the p3737-382 polypeptide was activating CD8 T cells in an HLA restricted manner, T cell lines generated with the three polypeptides used in Figure 3 were assayed for peptide-specific reactivity or lytic activity in the presence of neutralizing HLA-A2 or HLA-ABC monoclonal antibodies. As shown in Figure 4A-B, the reactivity, as assessed by IFN-y release, of the p373-382-generated T cells was 25 markedly suppressed by inclusion of either antibody as compared to T cells treated with control isotyped matched antibody. In parallel, it also was observed that neutralizing HLA-A2 or HLA-ABC monoclonal antibodies blocked lysis of tumor cells by p373-382 generated T cells as shown in Figures 4C-D, respectively. The findings described in the preceding three paragraphs were repeated two to 30 four times using T cells generated from two to three HLA-A2 donors. 12 WO 2013/123424 PCT/US2013/026484 Algorithms were used to determine the potential for other HLA alleles, in addition to HLA-A2, to bind to p373-382 or some other embedded polypeptide. The algorithms used were SYPE ITHI and NetMHCpan. The results of this investigation suggest that p373-382 or some fragments may bind other HLA class molecules (Table 2). Table 2. Epitopes predicted within p373-382 HLA Polymorphism Octamers Nonamers Decamers HLA-A*0201 -- -- SLAFLPESFD HLA-A*03 -- -- SLAFLPESFD HLA-A*1101 -- -- SLAFLPESFD HLA-A*2402 -- SLAFLPESF - HLA-A*26 -- SLAFLPESF - HLA-B*08 LAFLPESF SLAFLPESF - HLA-B*14 -- SLAFLPESF - HLA-B*1501 -- SLAFLPESF SLAFLPESFD HLA-B*18 SLAFLPES SLAFLPESF - HLA-B*2705 -- SLAFLPESF - HLA-B*37 LAFLPESF SLAFLPESF - HLA-B*4402 -- SLAFLPESF - HLA-B*5101 LAFLPESF LAFLPESFD - HLA-C*01041 LAFLPESF -- - Algorithm: SYFPEITHI [world wide web at "syfpeithi.de/"], Threshold Score: 10 Algorithm: NetMHCpan [world wide web at "cbs.dtu.dk/"], Threshold 5% -- None 5 Taken together, the results provided herein demonstrate that p373-382 (SLAFLPESFD) serves as a prime candidate for cancer vaccines and therapeutics for HER-2/neu patients. p373-382 is processed in vitro by cellular enzymes, and it binds a prevalent MHC class I molecule, HLA-A2. CD8' T cells from human blood can be generated against this polypeptide, and these T cells can recognize breast cancer cells, 10 indicating that breast cancer cells are naturally processing p373-382 from the expressed HER-2/neu polypeptide and presenting p373-382 on the cell surface in the context of HLA-A*0201. OTHER EMBODIMENTS 15 It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. 20 13
    权利要求:
    Claims (17)
    [1] 1. A polypeptide, wherein the sequence of said polypeptide consists of the amino acid sequence set forth in SEQ ID NO: 1. 5
    [2] 2. A vaccine composition comprising a polypeptide, wherein the sequence of said polypeptide consists of the amino acid sequence set forth in SEQ ID NO: 1.
    [3] 3. The vaccine composition of claim 2, wherein said composition comprises an 10 adjuvant.
    [4] 4. The vaccine composition of claim 3, wherein said adjuvant is an oil and water mixture. 15
    [5] 5. The vaccine composition of claim 3, wherein said adjuvant is Montanide ISA-51.
    [6] 6. The vaccine composition of claim 2, wherein said composition comprises IL-2, IL-12, GM-CSF, or rintatolimod. 20
    [7] 7. A method for increasing the number of CD8' T cells having the ability to kill cancer cells expressing a HER2/neu polypeptide, wherein said method comprises contacting a population of CD8' T cells with a polypeptide, wherein the sequence of said polypeptide consists of the amino acid sequence set forth in SEQ ID NO: 1. 25
    [8] 8. The method of claim 7, wherein said contacting step occurs in an ex vivo manner.
    [9] 9. The method of claim 7, wherein said contacting step occurs in an in vivo manner.
    [10] 10. A method for increasing, within a human, the number of CD8' T cells having the 30 ability to kill cancer cells expressing a HER2/neu polypeptide, wherein said method comprises administering a vaccine composition to said human, wherein said composition 14 WO 2013/123424 PCT/US2013/026484 comprises a polypeptide, wherein the sequence of said polypeptide consists of the amino acid sequence set forth in SEQ ID NO: 1.
    [11] 11. The method of claim 10, wherein said human contains cancer cells expressing 5 said HER2/neu polypeptide.
    [12] 12. The method of claim 10, wherein said composition comprises an adjuvant.
    [13] 13. The method of claim 12, wherein said adjuvant is an oil and water mixture. 10
    [14] 14. The method of claim 12, wherein said adjuvant is Montanide ISA-5 1.
    [15] 15. The method of claim 10, wherein said composition comprises IL-2, IL-12, GM CSF, or rintatolimod. 15
    [16] 16. The method of claim 10, wherein said method comprises administering IL-2, IL 12, GM-CSF, rintatolimod, or a combination thereof to said human.
    [17] 17. The method of claim 10, wherein said method further comprises administering 20 trastuzumab to said human. 15
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    法律状态:
    2017-07-27| FGA| Letters patent sealed or granted (standard patent)|
    优先权:
    申请号 | 申请日 | 专利标题
    US201261600480P| true| 2012-02-17|2012-02-17||
    US61/600,480||2012-02-17||
    PCT/US2013/026484|WO2013123424A1|2012-02-17|2013-02-15|Methods and materials for generating cd8+ t cells having the ability to recognize cancer cells expressing a her2/neu polypeptide|
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