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Antineoplastic Effects of Partially HLA-Matched Irradiated Blood Mononuclear Cells in Patients With Renal Cell Carcinoma

Roger K. Strair, Dale Schaar, Daniel Medina, Mary B. Todd, Joseph Aisner, Robert S. DiPaola, Jacqueline Manago, Beth Knox, Amanda Jenkinson, Rachelle Senzon, Christina Baker, Liesel Dudek, Marie Ciardella, Mercy Kuriyan, Arnold Rubin, Edmund C. Lattime

From the Divisions of Medical Oncology and Surgical Oncology, and the Clinical Research Office, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ.

Address reprint requests to Roger K. Strair, MD, PhD, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, 195 Little Albany St, New Brunswick, NJ 08903; e-mail: strairrk{at}umdnj.edu.

	ABSTRACT

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Purpose: Vaccines, cytokines, and other biologic-based therapies are being developed as antineoplastic agents. Many of these agents are designed to induce an autologous immune response directed against the malignancy. In contrast, hematopoietic stem-cell transplantation is being developed as a form of allogeneic immunotherapy. This study tests the tolerance and antineoplastic activity of sequential infusions of partially HLA-matched allogeneic blood mononuclear cells (obtained from relatives) when administered outside of the context of a hematopoietic stem-cell transplantation. The cells are irradiated to prevent graft-versus-host disease.

Patients and Methods: Fifteen patients with relapsed or refractory malignancies for which no standard therapy was available were enrolled onto a clinical trial designed to assess the tolerability and antineoplastic effects of irradiated partially HLA-matched blood mononuclear cells obtained from relatives.

Results: There was disease regression in three patients with metastatic renal cell carcinoma during treatment. There was disease progression in six patients with metastatic renal cell carcinoma and two patients with metastatic melanoma during treatment. There was no change in disease state in several other patients.

Conclusion: Irradiated allogeneic blood mononuclear cells administered outside the context of hematopoietic stem-cell transplantation may induce disease responses in patients with relapsed or refractory malignancies. Transfusion of irradiated allogeneic blood mononuclear cells should be developed further as a novel therapeutic antineoplastic approach.

	INTRODUCTION

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IMMUNOTHERAPEUTIC APPROACHES to cancer include administration of immune regulatory cytokines, such as interleukin-2 (IL-2) or interferon alfa; administration of monoclonal antibodies directed against tumor-associated antigens; immunization with tumor-associated antigens or vectors designed to express such antigens; immunization with modified tumor cells or lysates; immunization with dendritic cells presenting tumor-associated antigens; adoptive transfer of cytotoxic T lymphocytes (CTLs); and allogeneic hematopoietic stem-cell transplantation.^1–4 The premise of each of these approaches is founded in animal models and human studies in which immune cells can recognize and kill tumor cells, or tumor-directed antibodies can result in protection from tumor growth or induce tumor regression.^1–4

Cancer therapies that are based on cytokines or immunization are designed to induce an autologous antitumor response. Successful application of these therapies must often overcome tumor-associated immunosuppressive mechanisms that support the development and growth of the tumor in the presence of an immune system (so-called immune tolerance or ignorance).^5–8 In contrast, successful allogeneic hematopoietic stem-cell transplantation for patients with acute and chronic leukemias, lymphomas, multiple myeloma, and renal cell carcinoma relies, at least in part, on donor-derived allogeneic CTL and/or natural killer (NK) cell detection of malignant cell major histocompatibility, minor histocompatibility, or tumor-specific antigen expression. Unfortunately, detection of these (or other) antigens on nonmalignant host-derived cells can result in severe graft-versus-host disease (GVHD).^4,9–12

The capacity of donor-derived lymphocytes to induce immunologically mediated disease responses after allogeneic hematopoietic stem-cell transplantation has led to the development of nonmyeloablative allogeneic stem-cell transplantations (NSTs) for patients with selected diseases.^4,10–12 In NST, the patient receives a conditioning regimen that is immunosuppressive and partially myelosuppressive but is not nearly as intense as the myeloablative conditioning used with standard allogeneic hematopoietic stem-cell transplantation. The immunosuppression in NST is administered to facilitate engraftment of donor hematopoietic cells. A hemato-lymphoid chimeric state is often achieved without the prolonged myelosuppression, mucositis, and other conditioning-related toxicities of a standard allogeneic transplantation. The engraftment of donor cells allows development of donor lymphocyte reactivity against host malignant cells. Standard GVHD may also develop. If there is neither tumor response nor significant GVHD, peritransplantation immunosuppression is withdrawn to enhance donor T-cell engraftment and reactivity. If necessary, additional donor lymphocytes can be infused to achieve tumor cell cytotoxicity. Such infusions may expand the donor T-cell repertoire or break immunologic tolerance. NST is under study in a wide range of hematologic and nonhematologic malignancies.^10–18 Nevertheless, NST is still an intensive therapy and many patients have either incomplete disease responses or persistent or progressive disease. Furthermore, the procedure results in significant morbidity and mortality as a consequence of long-term immunosuppression, a high incidence of infection, and GVHD.

The success of NST prompted the development of other novel allogeneic immunotherapies for patients with relapsed or refractory malignancies. The capacity of donor-derived immune cells to mediate tumor cytotoxicity outside the context of hematopoietic stem-cell transplantation was tested in a clinical trial of HLA-identical lymphocyte infusion from related donors. Minor disease responses were seen in patients with multiple myeloma and Hodgkin’s disease; a complete remission of Hodgkin’s disease was also seen. Serious GVHD occurred in two patients. One patient died as a result of treatment-related adverse effects similar to transfusion-associated GVHD.¹⁹ This study demonstrated antineoplastic activity mediated by HLA-identical donor lymphocytes administered after treatment with low-dose interferon alfa or cyclophosphamide, but without preceding allogeneic hematopoietic stem-cell transplantation and without the intent of durable engraftment. Nevertheless, response rates were low, and the toxicity was significant. Refinement of this procedure will require enhancement of response rate and suppression of GVHD.

The use of cellular therapy to mediate tumor-specific cytotoxicity without GVHD or prolonged immunosuppression may be achievable with autologous tumor-specific T-cell or NK cell clones,^1,20 allogeneic T or NK cells with a high degree of specificity for host-derived malignant cells,²¹ or, theoretically, unselected allogeneic T or NK cells incapacitated with respect to GVHD.

We chose to test the immunotherapeutic potential of unselected allogeneic donor cells using ex vivo cell irradiation to prevent GVHD. Irradiation of cellular blood products is widely used to prevent transfusion-associated GVHD and also has been studied in the context of hematopoietic stem-cell transplantation.^22–24 Irradiation does not impair cell-mediated cytotoxicity but prevents clonal expansion (and durable engraftment) of activated T cells or NK cells.^23–26 Prevention of GVHD with donor cell irradiation allows the use of donor cells with a high degree of HLA disparity with host cells.

The intent of our pilot study was to determine if infusions of irradiated allogeneic cells from a partially HLA-matched related donor would be well tolerated and result in tumor response. Potential mechanisms resulting in tumor response without engraftment of donor cells include direct effects of the infused irradiated donor cells (T or NK cells) on the host-derived malignant cells or an impact of the infused cells on immune tolerance or ignorance. If the treatment was well tolerated but no tumor response was seen, we planned a follow-up trial to test the tolerability and efficacy of irradiated allogeneic T-cell clones or NK cells directed against the malignant cell.

This article describes disease responses in three patients with metastatic renal cell carcinoma who were treated with irradiated allogeneic blood mononuclear cells in our pilot study. The disease response in these patients occurred in the absence of significant morbidity, the need for hospitalization, or evidence of organ dysfunction. Hence, treatment with irradiated allogeneic blood mononuclear cells obtained from related donors can result in disease regression and should be developed further as a novel form of immunotherapy associated with minimal toxicity.

	PATIENTS AND METHODS

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Patient and Donor Eligibility
Informed consent was obtained from all patients and donors under guidelines established by the Institutional Review Board of Robert Wood Johnson Medical School (New Brunswick, NJ) and in accordance with an assurance filed with and approved by the Department of Health and Human Services. Patient-donor matching was based on serologic analysis of major histocompatibility complex class I antigens. Each patient had a malignancy that was either relapsed or refractory to standard therapy, or the patient was not a candidate for standard therapy (ie, standard therapy was not available or the patient was ineligible for standard therapy because of comorbidities). Patient eligibility also included an Eastern Cooperative Oncology Group performance status of 0 to 2, a bilirubin level less than 1.5 x upper limit of normal, an AST level less than 3.0 x upper limit of normal, and a cardiac ejection fraction greater than 35%. After the first patient was treated, the protocol was amended to exclude patients with active CNS metastases. Patients with metastatic CNS disease were then eligible after primary irradiation or other CNS-directed therapy. Donors were screened with standard blood donation testing, an ECG, a medical history, and a physical examination.

Treatment Protocol
Donors who met standard blood donation criteria underwent 12- to 15-L leukapheresis via peripheral veins. Blood mononuclear cells were processed by irradiation (25 Gy) and immediately infused. All patients received acetaminophen and diphenhydramine before administration of the cells. Formal disease evaluation was undertaken 5 to 6 weeks after each infusion. Repeat infusions were undertaken every 8 weeks. Initial patients were required to have disease response (partial response according to the National Cancer Institute Response Evaluation Criteria in Solid Tumors Group) after the second infusion to continue on therapy. Subsequent patients with stable disease were eligible to receive sequential doses of irradiated donor lymphocytes every 8 weeks until there was evidence of disease progression (according to National Cancer Institute Response Evaluation Criteria in Solid Tumors Group criteria). Radiographic studies were interpreted by both a radiologist and the study principal investigator (R.K.S).

	RESULTS

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Patients and Donors
Fifteen patients have so far been treated as part of this ongoing trial of irradiated donor lymphocytes for patients with relapsed or refractory malignancies. Each patient either had a malignancy refractory to standard therapies or was judged not to be a candidate for standard therapies. The disease profile included metastatic renal cell carcinoma (11 patients), metastatic melanoma (two patients), and acute myelogenous leukemia (AML; two patients). In all patients, a haploidentical or partially HLA-matched donor was selected on the basis of patient-donor convenience, the results of blood bank donation screening, and the degree of HLA mismatch. Donors with ABO compatibility and predicted NK alloreactivity as a consequence of killer immunoglobulin-like receptor (KIR) mismatch were preferentially used. There were no toxicities associated with leukapheresis. All products were irradiated (25 Gy) before infusion. All patients received 0.9 to 3.6 x 10⁸ CD3⁺ cells/kg/infusion.

Adverse Effects
There were no infusional toxicities. Three patients developed fever within 24 hours of infusion. In all patients, the fevers spontaneously resolved by 72 hours without specific therapy. The first patient to develop a fever was admitted to the hospital for observation. No manifestations of GVHD were apparent in any patient. Transient asymptomatic elevation of hepatic ALT or AST occurred in two patients. Two patients were hospitalized in association with symptomatic progressive disease.

Tumor Responses
The patient profile and results of treatment are presented in Table 1. Three patients with metastatic renal cell carcinoma had tumor responses. One patient (patient 1) had radiographic evidence of tumor reduction in both lung and liver after the second infusion (Fig 1). Unfortunately, CNS symptoms became apparent before the scheduled third administration, radiographic studies revealed brain metastases, and the patient was removed from study to undergo CNS irradiation. The clinical protocol was subsequently amended to include initial brain computed tomography or magnetic resonance imaging staging and treatment (irradiation) of detected metastases before enrollment. A second patient with metastatic renal cell carcinoma (patient 3) had a tumor response detected after the third infusion and has ongoing response after the fourth infusion, 11 months after initiation of treatment (6 months after first documentation of response; Fig 2). A third patient with metastatic renal cell carcinoma had tumor reduction after the second infusion and is continuing to receive therapy (Fig 3). Two patients with metastatic renal cell carcinoma who were enrolled during the early stages of the study had stable disease after two treatments and were removed from the study as mandated by the clinical protocol. Subsequently, the protocol was amended to allow patients with stable disease to continue therapy. Six other patients with metastatic renal cell carcinoma had progressive disease after one or two infusions. Two patients with metastatic melanoma had progressive disease after two treatments. One of these patients had improvement in pulmonary symptoms and lung positron emission tomography scan but developed new sites of soft-tissue and lymph node disease during treatment. Two patients with relapsed refractory AML had stable disease after three infusions but were removed from the study to undergo different therapies.

View larger version (105K): [in this window] [in a new window]   Fig 1. Tumor response after administration of irradiated blood mononuclear cells to patient 1. (A) Baseline computed tomography (CT) scan images. (B) Corresponding CT images after second infusion of irradiated blood mononuclear cells. Arrows indicate sites of metastatic disease.

View larger version (96K): [in this window] [in a new window]   Fig 2. Tumor response after administration of irradiated blood mononuclear cells to patient 3. (A) Baseline computed tomography (CT) scan. (B and C) Corresponding CT images after third and fourth infusions. Arrows indicate sites of metastatic disease.

View larger version (69K): [in this window] [in a new window]   Fig 3. Tumor response after administration of irradiated blood mononuclear cells to patient 14. (A) Baseline computed tomography (CT) scan. (B) Corresponding CT image after second infusion of irradiated blood mononuclear cells.

	DISCUSSION

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Patients with metastatic renal cell carcinoma are often treated with interferon alfa and/or IL-2. Tumor response after intensive therapy with high doses of IL-2 ranges from 10% to 35%, with 5% to 10% of treatments resulting in complete response, many of which are durable.^1,27–31 However, high degrees of toxicity, including a dose-related vascular leak syndrome that results in hypotension, multiple organ system dysfunction, and frequent need for intensive care, are major drawbacks of this therapy.^27–31 Lower doses of IL-2 are better tolerated, but durable responses are seen less frequently.^1,30,31

NST from an HLA-identical related donor has recently been evaluated as therapy for patients with metastatic renal cell carcinoma. These transplantations are undertaken after administration of an immunosuppressive regimen that has no apparent direct cytotoxicity on the renal cell carcinoma. Donor cells are then administered, and on engraftment, hematopoiesis in the recipient becomes chimeric and generally evolves to a full donor cell complement of hematopoietic-derived blood cells. The immunologic basis of this therapy is suggested by kinetic parameters of disease response. Regression of tumor is generally delayed until full donor T-cell chimerism is achieved, often in conjunction with withdrawal of immunosuppressive medications, the presence of GVHD, and/or the use of posttransplantation adoptive transfer of donor lymphocytes. Although the conditioning therapy used before NST is much better tolerated than that used in fully ablative transplantation, there is significant transplantation-related morbidity and mortality caused by immunosuppression, other complexities of medical therapy, and GVHD. Furthermore, only a minority of patients have HLA-identical donors, and the majority of patients with renal cell carcinoma treated with NST have had no response or incomplete response to treatment.^4,13–18 In the context of these features, the tumor responses seen after infusion of irradiated partially HLA-matched lymphocytes obtained from related donors in our study is notable for the simplicity of the therapy, the relatively low financial cost, the availability of an expanded donor pool (compared with NST), and the low rate of adverse effects.

Although spontaneous remissions of renal cell carcinoma have been described, they occur infrequently.^32,33 Therefore, the three tumor responses seen in our study are likely related to therapy. Of note, the tumor responses in our study were delayed for several months after initiation of treatment. This delay is reminiscent of an immune-mediated reaction, similar to those seen after NST for patients with metastatic renal cell carcinoma. However, in our study, the infused cells have a short half-life, and irradiation prevents clonal expansion of lymphocytes.^19,22–26 Therefore, it is possible that a subset of the infused cells (eg, NK cells, T cells, macrophages) are mediating a direct effect on the tumor cell that results in delayed cell death; mediating a direct effect on the tumor cell that results in delayed cytotoxicity by autologous lymphocytes; immunizing the host against a cross-reactive donor derived antigen; or inducing an adjuvant, proinflammatory effect that affects host immune cells in a fashion that results in breaking autologous immune tolerance or ignorance of the tumor cells.

The development of a tumor in the context of a functioning immune system implies that the malignant cells do not induce autologous immune-mediated cytotoxicity. This immune tolerance or ignorance may be due to rapid tumor growth, lack of tumor-specific antigen presentation by appropriate cells in the right context, lack of the proinflammatory cytokine milieu necessary for production and activity of cytotoxic T cells or NK cells, the presence of tumor-derived products that inhibit immune reactivity, or the lack of expression of surface molecules necessary to induce NK-cell–mediated cytotoxicity.^5–9 Some tumor cells may actively induce immune tolerance or ignorance by altering their environment with production of locally immunosuppressive mediators, such as IL-10, transforming growth factor beta, or prostaglandin E2.^34–36 Each of these mechanisms may be altered by the infusion of irradiated allogeneic lymphocytes.

With respect to NK cells, host-donor incompatibility for KIR has been implicated in the efficacy of haploidentical bone marrow transplantations for patients with high-risk AML.^37–40 NK clones with KIR incompatibility have also been shown to be able to mediate cytotoxic effects against renal cell carcinoma cells.⁴⁰ In our study, one patient with a disease response was KIR compatible with donor cells, whereas the other two patients with tumor response were not.

One novel aspect of therapy with irradiated allogeneic lymphocytes relates to the delay in tumor response, despite irradiation of the cells. Lymphocyte-mediated cytotoxicity in the absence of long-term engraftment has been demonstrated in animal models. For example, a single infusion of NK alloreactive cells eliminates human leukemia in a nonobese diabetic–severe combined immunodeficient model,³⁹ and irradiated CTL lines retain cytotoxicity despite irradiation.^22–26 Human studies also demonstrate cytotoxicity in the absence of long-term engraftment: Tumor responses have been seen after irradiated donor lymphocyte infusions following hematopoietic stem-cell transplantation,⁴¹ and durable tumor responses have been seen despite subsequent rejection of hematopoietic cell transplants.⁴² In addition, donor-derived alloreactive NK cells, highly associated with the lack of relapse after a haploidentical transplantation for AML, are not detected for more than 4 months after transplantation.^35–37 Perhaps the irradiated cells (eg, T cells and NK cells) can target the tumor and initiate a cascade of cellular and cytokine-mediated effects that result in tumor cell cytotoxicity despite the absence of long-term engraftment. Alternatively, irradiated allogeneic cells may trigger inflammatory responses that result in alteration of host immune reactivity (eg, break immune tolerance or ignorance, or expose new antigens on the malignant cell).

Adoptive immunotherapy with haploidentical allogeneic blood lymphocytes has been reported previously in conjunction with chemotherapy⁴³ or following autologous bone marrow transplantation with and without IL-2.⁴⁴ A single disease response was noted in conjunction with chemotherapy when administered to a patient with a non-Hodgkin’s lymphoma,⁴³ and use with autologous bone marrow transplantation and IL-2 resulted in severe toxicity.⁴⁴ In addition, irradiated unrelated donor lymphocytes in combination with rituximab have been used to treat posttransplantation lymphoproliferative disease occurring after mismatched donor transplantation.⁴⁵ In our study the allogeneic cells were administered in the absence of any conditioning or concurrent antineoplastic therapy, and the cells were irradiated to prevent durable engraftment and toxicity. Hence, chemotherapy or antibody therapy does not confound analysis of disease response, and only minor reversible adverse events were detected.

Although too few patients with renal cell carcinoma have been treated to determine frequency of response, duration of response, or patient-specific parameters predicting antineoplastic efficacy, the lack of toxicity, the logistic ease of the treatment, the relatively low financial cost of therapy, and the broad availability of related donors—partially HLA-matched cells were used—make this treatment suitable for additional study. Hence, many patients with metastatic renal cell carcinoma not eligible for frequently used therapies (such as high-dose IL-2) or experimental therapies (such as NST) might be candidates for studies incorporating the use of irradiated partially HLA-matched donor lymphocytes. Future areas of study include defining the spectrum of malignancies susceptible to such therapy, disease-specific response rates and duration of response, the mechanism by which irradiated allogeneic cells mediate antineoplastic effects, the potential for use of irradiated lymphocytes (or related therapies) as a component of combination therapy, the impact of alternate treatment schedules, and the range of HLA incompatibilities or alternate antigenic stimuli that can be used in such treatment. Ideally, this preliminary report will stimulate additional research that enhances our understanding of the biology and application of this well-tolerated therapy.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, and the University of Medicine and Dentistry of New Jersey.

	REFERENCES

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Submitted May 14, 2003; accepted July 30, 2003.

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