Systemic T cell adoptive immunotherapy of malignant gliomas

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Object. To determine the feasibility, toxicity, and potential therapeutic benefits of systemic adoptive immunotherapy, 10 patients with progressive primary or recurrent malignant glioma received this treatment. Adoptive immunotherapy, the transfer of immune T lymphocytes, is capable of mediating the regression of experimental brain tumors in animal models. In animal models, lymph nodes (LNs) that drain the tumor vaccine site are a rich source of tumor-immune T cells.

Methods. In this clinical study, patients were inoculated intradermally with irradiated autologous tumor cells and granulocyte macrophage-colony stimulating factor as an adjuvant. Cells from draining inguinal LNs, surgically resected 7 days after vaccination, were stimulated sequentially with staphylococcal enterotoxin A and anti-CD3, and a low dose of interleukin-2 (60 IU/ml) was used to expand the stimulated cells. The maximum cell proliferation was 350-fold over 10 days of culture. The activated cells were virtually all T cells consisting of various proportions of CD4 and CD8 cells. These cells were given to patients by intravenous infusion at doses ranging from 9 × 108 to 1.5 × 1011. There were no Grade 3 or 4 toxicities associated with the treatment. Following T-cell transfer therapy, radiographic regression that lasted at least 6 months was demonstrated in two patients with recurrent tumors. One patient demonstrated stable disease that has lasted for more than 17 months. The remaining patients had progressive disease; however, four of the eight patients with recurrent tumor remain alive more than 1 year after surgery for recurrence. Three patients required intervention with corticosteroid agents or additional surgery approximately 1 month following cell transfer.

Conclusions. These intriguing clinical observations warrant further trials to determine whether this approach can provide therapeutic benefits and improve survival.

Article Information

Address reprint requests to: Suyu Shu, Ph.D., Center for Surgery Research FF5, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195.

© AANS, except where prohibited by US copyright law.

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    Case 3. Serial MR images obtained following surgery for tumor recurrence (A), prior to immunotherapy (B), and following T-cell transfer, at 1 month (C), 2 months (D), 4 months (E), and 6 months (F).

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    Case 7. Serial MR images obtained following surgery for tumor recurrence (A), prior to immunotherapy (B), and following T-cell transfer, at 1 month (C), 3 months (D), 5 months (E), and 7 months (F).

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    Case 9. Serial MR images obtained following surgery for tumor recurrence (A), prior to immunotherapy (B), and following T-cell transfer, at 1 month (C ), 3 months (D), 5 months (E), and 7 months (F).

References

1.

Alexander JPKudoh SMelsop KAet al: T-cells infiltrating renal cell carcinoma display a poor proliferative response even though they can produce interleukin 2 and express interleukin 2 receptors. Cancer Res 53:138013871993Alexander JP Kudoh S Melsop KA et al: T-cells infiltrating renal cell carcinoma display a poor proliferative response even though they can produce interleukin 2 and express interleukin 2 receptors. Cancer Res 53:1380–1387 1993

2.

Arca MJKrauss JCAruga Aet al: Therapeutic efficacy of T cells derived from lymph nodes draining a poorly immunogenic tumor transduced to secrete granulocyte-macrophage colony-stimulating factor. Cancer Gene Ther 3:39471996Arca MJ Krauss JC Aruga A et al: Therapeutic efficacy of T cells derived from lymph nodes draining a poorly immunogenic tumor transduced to secrete granulocyte-macrophage colony-stimulating factor. Cancer Gene Ther 3:39–47 1996

3.

Barba DSaris SCHolder Cet al: Intratumoral LAK cell and interleukin-2 therapy of human gliomas. J Neurosurg 70:1751821989Barba D Saris SC Holder C et al: Intratumoral LAK cell and interleukin-2 therapy of human gliomas. J Neurosurg 70:175–182 1989

4.

Boiardi ASilvani ARuffini PAet al: Loco-regional immunotherapy with recombinant interleukin-2 and adherent lymphokine-activated killer cells (A-LAK) in recurrent glioblastoma patients. Cancer Immunol Immunother 39:1931971994Boiardi A Silvani A Ruffini PA et al: Loco-regional immunotherapy with recombinant interleukin-2 and adherent lymphokine-activated killer cells (A-LAK) in recurrent glioblastoma patients. Cancer Immunol Immunother 39:193–197 1994

5.

Brem HPiantadosi SBurger PCet al: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345:100810121995Brem H Piantadosi S Burger PC et al: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345:1008–1012 1995

6.

Brooks WHCaldwell HDMorata RH: Immune responses in patients with gliomas. Surg Neurol 2:4194231974Brooks WH Caldwell HD Morata RH: Immune responses in patients with gliomas. Surg Neurol 2:419–423 1974

7.

Brooks WHNetsky MGNormansell DEet al: Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor. J Exp Med 136:163116471972Brooks WH Netsky MG Normansell DE et al: Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor. J Exp Med 136:1631–1647 1972

8.

Castelli MGChiabrando CFanelli Ret al: Prostaglandin and thromboxane synthesis by human intracranial tumors. Cancer Res 49:150515081989Castelli MG Chiabrando C Fanelli R et al: Prostaglandin and thromboxane synthesis by human intracranial tumors. Cancer Res 49:1505–1508 1989

9.

Chachoua AOratz RLiebes Let al: Phase Ib trial of granulocyte-macrophage colony-stimulating factor combined with murine monoclonal antibody R24 in patients with metastatic melanoma. J Immunother 16:1321411994Chachoua A Oratz R Liebes L et al: Phase Ib trial of granulocyte-macrophage colony-stimulating factor combined with murine monoclonal antibody R24 in patients with metastatic melanoma. J Immunother 16:132–141 1994

10.

Chang AEAruga ACameron MJet al: Adoptive immunotherapy with vaccine-primed lymph node cells secondarily activated with anti-CD3 and interleukin-2. J Clin Oncol 15:7968071997Chang AE Aruga A Cameron MJ et al: Adoptive immunotherapy with vaccine-primed lymph node cells secondarily activated with anti-CD3 and interleukin-2. J Clin Oncol 15:796–807 1997

11.

Chang AEYoshizawa HSakai Ket al: Clinical observations on adoptive immunotherapy with vaccine-primed T-lymphocytes secondarily sensitized to tumor in vitro. Cancer Res 53:104310501993Chang AE Yoshizawa H Sakai K et al: Clinical observations on adoptive immunotherapy with vaccine-primed T-lymphocytes secondarily sensitized to tumor in vitro. Cancer Res 53:1043–1050 1993

12.

Chou TChang AEShu S: Generation of therapeutic T lymphocytes from tumor-bearing mice by in vitro sensitization. Culture requirements and characterization of immunologic specificity. J Immunol 140:245324611988Chou T Chang AE Shu S: Generation of therapeutic T lymphocytes from tumor-bearing mice by in vitro sensitization. Culture requirements and characterization of immunologic specificity. J Immunol 140:2453–2461 1988

13.

Disis MLBernhard HShiota FMet al: Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines. Blood 88:2022101996Disis ML Bernhard H Shiota FM et al: Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines. Blood 88:202–210 1996

14.

Dranoff GJaffee ELazenby Aet al: Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony stimulating factor stimulates potent, specific and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 90:353935431993Dranoff G Jaffee E Lazenby A et al: Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony stimulating factor stimulates potent specific and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 90:3539–3543 1993

15.

Fakhrai HDorigo OShawler DLet al: Eradication of established intracranial rat gliomas by transforming growth factor β antisense gene therapy. Proc Natl Acad Sci USA 93:290929141996Fakhrai H Dorigo O Shawler DL et al: Eradication of established intracranial rat gliomas by transforming growth factor β antisense gene therapy. Proc Natl Acad Sci USA 93:2909–2914 1996

16.

Finke JHZea AHStanley Jet al: Loss of T-cell receptor ζ chain and p56lck in T-cells infiltrating human renal cell carcinoma. Cancer Res 53:561356161993Finke JH Zea AH Stanley J et al: Loss of T-cell receptor ζ chain and p56lck in T-cells infiltrating human renal cell carcinoma. Cancer Res 53:5613–5616 1993

17.

Goedegebuure PSDouville LMLi Het al: Adoptive immunotherapy with tumor-infiltrating lymphocytes and interleukin-2 in patients with metastatic malignant melanoma and renal cell carcinoma: a pilot study. J Clin Oncol 13:193919491995Goedegebuure PS Douville LM Li H et al: Adoptive immunotherapy with tumor-infiltrating lymphocytes and interleukin-2 in patients with metastatic malignant melanoma and renal cell carcinoma: a pilot study. J Clin Oncol 13:1939–1949 1995

18.

Hayes RLKoslow MHiesiger EMet al: Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma. Cancer 76:8408521995Hayes RL Koslow M Hiesiger EM et al: Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma. Cancer 76:840–852 1995

19.

Head JRGriffin WST: Functional capacity of solid tissue implants in the brain: evidence for immunological privilege. Proc R Soc B 224:3753871985Head JR Griffin WST: Functional capacity of solid tissue implants in the brain: evidence for immunological privilege. Proc R Soc B 224:375–387 1985

20.

Huettner CPaulus WRoggendorf W: Messenger RNA expression of the immunosuppressive cytokine IL-10 in human gliomas. Am J Pathol 146:3173221995Huettner C Paulus W Roggendorf W: Messenger RNA expression of the immunosuppressive cytokine IL-10 in human gliomas. Am J Pathol 146:317–322 1995

21.

Inge THHoover SKSusskind BMet al: Inhibition of tumor-specific cytotoxic T-lymphocyte responses by transforming growth factor ß1. Cancer Res 52:138613921992Inge TH Hoover SK Susskind BM et al: Inhibition of tumor-specific cytotoxic T-lymphocyte responses by transforming growth factor ß1. Cancer Res 52:1386–1392 1992

22.

Inoue MPlautz GEShu S: Treatment of intracranial tumors by systemic transfer of superantigen-activated tumor-draining lymph node T cells. Cancer Res 56:470247081996Inoue M Plautz GE Shu S: Treatment of intracranial tumors by systemic transfer of superantigen-activated tumor-draining lymph node T cells. Cancer Res 56:4702–4708 1996

23.

Jacobs SKWilson DJKornblith PLet al: Interleukin-2 and autologous lymphokine-activated killer cells in the treatment of malignant glioma. J Neurosurg 64:7437491986Jacobs SK Wilson DJ Kornblith PL et al: Interleukin-2 and autologous lymphokine-activated killer cells in the treatment of malignant glioma. J Neurosurg 64:743–749 1986

24.

Jager ERinghoffer MDienes HPet al: Granulocyte-macrophage-colony-stimulating factor enhances immune responses to melanoma-associated peptides in vivo. Int J Cancer 67:54621996Jager E Ringhoffer M Dienes HP et al: Granulocyte-macrophage-colony-stimulating factor enhances immune responses to melanoma-associated peptides in vivo. Int J Cancer 67:54–62 1996

25.

Kruse CASchiltz PMBellgrau Det al: Intracranial administrations of single or multiple source allogeneic cytotoxic T lymphocytes: chronic therapy for primary brain tumors. J Neurooncol 19:1611681994Kruse CA Schiltz PM Bellgrau D et al: Intracranial administrations of single or multiple source allogeneic cytotoxic T lymphocytes: chronic therapy for primary brain tumors. J Neurooncol 19:161–168 1994

26.

Kwak LWYoung HAPennington RWet al: Vaccination with syngeneic, lymphoma-derived immunoglobulin idiotype combined with granulocyte/macrophage colony-stimulating factor primes mice for a protective T-cell response. Proc Natl Acad Sci USA 93:10972109771996Kwak LW Young HA Pennington RW et al: Vaccination with syngeneic lymphoma-derived immunoglobulin idiotype combined with granulocyte/macrophage colony-stimulating factor primes mice for a protective T-cell response. Proc Natl Acad Sci USA 93:10972–10977 1996

27.

Lillehei KOMitchell DHJohnson SDet al: Long-term follow-up of patients with recurrent malignant gliomas treated with adjuvant adoptive immunotherapy. Neurosurgery 28:16221991Lillehei KO Mitchell DH Johnson SD et al: Long-term follow-up of patients with recurrent malignant gliomas treated with adjuvant adoptive immunotherapy. Neurosurgery 28:16–22 1991

28.

Mahaley MS JrBrooks WHRoszman TLet al: Immunobiology of primary intracranial tumors. Part 1: studies of the cellular and humoral general immune competence of brain-tumor patients. J Neurosurg 46:4674761977Mahaley MS Jr Brooks WH Roszman TL et al: Immunobiology of primary intracranial tumors. Part 1: studies of the cellular and humoral general immune competence of brain-tumor patients. J Neurosurg 46:467–476 1977

29.

Matsumura TSussman JJKrinock RAet al: Characteristics and in vivo homing of long-term T-cell lines and clones derived from tumor-draining lymph nodes. Cancer Res 54:274427501994Matsumura T Sussman JJ Krinock RA et al: Characteristics and in vivo homing of long-term T-cell lines and clones derived from tumor-draining lymph nodes. Cancer Res 54:2744–2750 1994

30.

Maxwell MGalanopoulos TNeville-Golden Jet al: Effect of the expression of transforming growth factor-β2 in primary human glioblastomas on immunosuppression and loss of immune surveillance. J Neurosurg 76:7998041992Maxwell M Galanopoulos T Neville-Golden J et al: Effect of the expression of transforming growth factor-β2 in primary human glioblastomas on immunosuppression and loss of immune surveillance. J Neurosurg 76:799–804 1992

31.

Medawar PW: Immunity to homologous grafted skin. III. The fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol 29:58691948Medawar PW: Immunity to homologous grafted skin. III. The fate of skin homografts transplanted to the brain to subcutaneous tissue and to the anterior chamber of the eye. Br J Exp Pathol 29:58–69 1948

32.

Merchant REMerchant LHCook SHSet al: Intralesional infusion of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) for the treatment of patients with malignant brain tumor. Neurosurgery 23:7257321988Merchant RE Merchant LH Cook SHS et al: Intralesional infusion of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) for the treatment of patients with malignant brain tumor. Neurosurgery 23:725–732 1988

33.

Peng LShu SKrauss JC: Treatment of subcutaneous tumor with adoptively transferred T cells. Cell Immunol 178:24321997Peng L Shu S Krauss JC: Treatment of subcutaneous tumor with adoptively transferred T cells. Cell Immunol 178:24–32 1997

34.

Plautz GEInoue MShu S: Defining the synergistic effects of irradiation and T-cell immunotherapy for murine intracranial tumors. Cell Immunol 171:2772841996Plautz GE Inoue M Shu S: Defining the synergistic effects of irradiation and T-cell immunotherapy for murine intracranial tumors. Cell Immunol 171:277–284 1996

35.

Plautz GETouhalisky JEShu S: Treatment of murine gliomas by adoptive transfer of ex vivo activated tumor-draining lymph node cells. Cell Immunol 178:1011071997Plautz GE Touhalisky JE Shu S: Treatment of murine gliomas by adoptive transfer of ex vivo activated tumor-draining lymph node cells. Cell Immunol 178:101–107 1997

36.

Rosenberg SAPackard BSAebersold PMet al: Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 319:167516801988Rosenberg SA Packard BS Aebersold PM et al: Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 319:1675–1680 1988

37.

Roszman TLBrooks WH: Immunobiology of primary intracranial tumors. III. Demonstration of a qualitative lymphocyte abnormality in patients with primary brain tumors. Clin Exp Immunol 39:3954021980Roszman TL Brooks WH: Immunobiology of primary intracranial tumors. III. Demonstration of a qualitative lymphocyte abnormality in patients with primary brain tumors. Clin Exp Immunol 39:395–402 1980

38.

Saris SCPatronas NJRosenberg SAet al: The effect of intravenous interleukin-2 on brain water content. J Neurosurg 71:1691741989Saris SC Patronas NJ Rosenberg SA et al: The effect of intravenous interleukin-2 on brain water content. J Neurosurg 71:169–174 1989

39.

Saris SCRosenberg SAFriedman RB: Penetration of recombinant interleukin-2 across the blood-cerebrospinal fluid barrier. J Neurosurg 69:29341988Saris SC Rosenberg SA Friedman RB: Penetration of recombinant interleukin-2 across the blood-cerebrospinal fluid barrier. J Neurosurg 69:29–34 1988

40.

Sawamura YHosokawa MKuppner MCet al: Antitumor activity and surface phenotypes of human glioma-infiltrating lymphocytes after in vitro expansion in the presence of interleukin 2. Cancer Res 49:184318491989Sawamura Y Hosokawa M Kuppner MC et al: Antitumor activity and surface phenotypes of human glioma-infiltrating lymphocytes after in vitro expansion in the presence of interleukin 2. Cancer Res 49:1843–1849 1989

41.

Shu SChou TRosenberg SA: Generation from tumor-bearing mice of lymphocytes with in vitro therapeutic efficacy. J Immunol 139:2953041987Shu S Chou T Rosenberg SA: Generation from tumor-bearing mice of lymphocytes with in vitro therapeutic efficacy. J Immunol 139:295–304 1987

42.

Shu SKrinock RAMatsumura Tet al: Stimulation of tumor-draining lymph node cells with superantigenic staphylococcal toxins leads to the generation of tumor-specific effector T cells. J Immunol 152:127712881994Shu S Krinock RA Matsumura T et al: Stimulation of tumor-draining lymph node cells with superantigenic staphylococcal toxins leads to the generation of tumor-specific effector T cells. J Immunol 152:1277–1288 1994

43.

Simons JWJaffee EMWeber CEet al: Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer. Cancer Res 57:153715461997Simons JW Jaffee EM Weber CE et al: Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer. Cancer Res 57:1537–1546 1997

44.

Sussman JJShu SSondak VKet al: Activation of T lymphocytes for the adoptive immunotherapy of cancer. Ann Surg Oncol 1:2963061994Sussman JJ Shu S Sondak VK et al: Activation of T lymphocytes for the adoptive immunotherapy of cancer. Ann Surg Oncol 1:296–306 1994

45.

Sussman JJWahl WLChang AEet al: Unique characteristics associated with systemic adoptive immunotherapy of experimental intracerebral tumors. J Immunother 18:35441995Sussman JJ Wahl WL Chang AE et al: Unique characteristics associated with systemic adoptive immunotherapy of experimental intracerebral tumors. J Immunother 18:35–44 1995

46.

Tao MHLevy R: Idiotype/granulocyte-macrophage colony-stimulating factor fusion protein as a vaccine for B-cell lymphoma. Nature 362:7557581993Tao MH Levy R: Idiotype/granulocyte-macrophage colony-stimulating factor fusion protein as a vaccine for B-cell lymphoma. Nature 362:755–758 1993

47.

Wahl WLSussman JJShu Set al: Adoptive immunotherapy of murine intracerebral tumors with anti-CD3/interleukin-2-activated tumor-draining lymph node cells. J Immunother 15:2422501994Wahl WL Sussman JJ Shu S et al: Adoptive immunotherapy of murine intracerebral tumors with anti-CD3/interleukin-2-activated tumor-draining lymph node cells. J Immunother 15:242–250 1994

48.

Walker MDAlexander E JrHunt WE: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative trial. J Neurosurg 49:3333431978Walker MD Alexander E Jr Hunt WE: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative trial. J Neurosurg 49:333–343 1978

49.

Walker MDGreen SBByar DPet al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant gliomas after surgery. N Engl J Med 303:132313291980Walker MD Green SB Byar DP et al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant gliomas after surgery. N Engl J Med 303:1323–1329 1980

50.

Yoshida STanaka RTakai Net al: Local administration of autologous lymphokine-activated killer cells and recombinant interleukin 2 to patients with malignant brain tumors. Cancer Res 48:501150161988Yoshida S Tanaka R Takai N et al: Local administration of autologous lymphokine-activated killer cells and recombinant interleukin 2 to patients with malignant brain tumors. Cancer Res 48:5011–5016 1988

51.

Yoshizawa HChang AEShu S: Specific adoptive immunotherapy mediated by tumor-draining lymph node cells sequentially activated with anti-CD3 and IL-2. J Immunol 147:7297371991Yoshizawa H Chang AE Shu S: Specific adoptive immunotherapy mediated by tumor-draining lymph node cells sequentially activated with anti-CD3 and IL-2. J Immunol 147:729–737 1991

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