Originally published as JCO Early Release 10.1200/JCO.2004.01.127 on August 16 2004

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Allogeneic Lymphocytes Induce Tumor Regression of Advanced Metastatic Breast Cancer

From the Experimental Transplantation and Immunology Branch and Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Diagnostic Radiology Department and Department of Transfusion Medicine, National Institutes of Health Clinical Center, Bethesda, MD.

Address reprint requests to Michael R. Bishop, MD, Experimental Transplantation and Immunology Branch, Center for Cancer Research/National Cancer Institute/National Institutes of Health, Building 10, Room 12N226, Bethesda, MD 20892; e-mail: mbishop{at}mail.nih.gov

	ABSTRACT

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PURPOSE: Allogeneic T lymphocytes can induce regression of metastatic breast cancer through an immune-mediated graft-versus-tumor (GVT) effect in murine models. To determine if a clinical GVT effect exists against metastatic breast cancer, allogeneic lymphocytes were used as adoptive cellular therapy after a reduced-intensity chemotherapy conditioning regimen and allogeneic hematopoietic stem-cell transplantation (HSCT) from human leukocyte antigen–matched siblings.

PATIENTS AND METHODS: Sixteen patients with metastatic breast cancer that had progressed after treatment with anthracyclines, taxanes, hormonal agents, and trastuzumab, received allogeneic HSCT. The reduced-intensity transplant conditioning regimen consisted of cyclophosphamide and fludarabine. To distinguish an immunological GVT effect from any antitumor effect of cytotoxic chemotherapy in the transplant-conditioning regimen, allogeneic T lymphocytes were removed from the stem-cell graft and were subsequently administered late postallogeneic HSCT. Allogeneic lymphocytes containing 1 x 10⁶, 5 x 10⁶, and 10 x 10⁶ CD3⁺ cells/kg were infused on days +42, +70, and +98 post–allogeneic HSCT, respectively.

RESULTS: Objective tumor regressions occurred after day +28 post–allogeneic HSCT in six patients and were attributed to allogeneic lymphocyte infusions. Two of these responding patients had disease progression post–allogeneic HSCT before subsequent tumor regression. Tumor regressions occurred concomitantly with the establishment of complete donor T-lymphoid engraftment, were associated with the development of graft-versus-host disease (GVHD), and were abrogated by subsequent systemic immunosuppression for GVHD.

CONCLUSION: Allogeneic lymphocytes can induce regression of advanced metastatic breast cancer. These results indicate that an immunological GVT effect from allogeneic lymphocytes exists against metastatic breast cancer and provide rationale for further development of allogeneic cellular therapy for this largely incurable disease.

	INTRODUCTION

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Metastatic breast cancer is a significant worldwide health problem; more than 40,000 women die each year from metastatic breast cancer in the United States alone.¹ Despite the use of hormonal therapy and chemotherapy, metastatic breast cancer is rarely cured.^2,3 The use of second- and third-line chemotherapeutic agents for metastatic breast cancer may result in clinically relevant responses; however, these responses are usually transient, and median survival after their administration is generally less than 24 months.⁴ The limited efficacy of second-line treatments in metastatic breast cancer has prompted the investigation of novel therapeutic strategies to complement currently available modalities.

For more than 40 years, there has been ongoing research on the treatment of metastatic breast cancer with immune-based therapies including vaccines, cytokines, monoclonal antibodies, and adoptive immunotherapy.^5-10 Despite laboratory and clinical evidence demonstrating that breast cancer is immunogenic, immune-based therapy has had limited efficacy in the treatment of metastatic breast cancer, with the remarkable exception of trastuzumab.^3,11,12 Adoptive cellular therapy with autologous T cells has been demonstrated to result in clinical responses in advanced melanoma patients, but there are minimal clinical data supporting its efficacy in metastatic breast cancer and other advanced solid tumors.^13,14

Allogeneic hematopoietic stem-cell transplantation (HSCT) is a form of adoptive cellular therapy that has a high degree of efficacy in hematologic malignancies, especially chronic myelogenous leukemia.¹⁵ The efficacy of allogeneic HSCT is primarily attributed to a T-cell–mediated response to host and/or tumor antigens, referred to as the graft-versus-tumor (GVT) effect. Despite evidence of an allogeneic GVT effect against metastatic breast cancer in murine models and anecdotal clinical reports, there had been limited enthusiasm to investigate allogeneic HSCT in metastatic breast cancer owing to the significant morbidity and mortality generally associated with this procedure.^16-21 However, the introduction of reduced-intensity transplant conditioning regimens, which are associated with decreased treatment-related toxicity, led to increased investigation of allogeneic HSCT in diseases, including solid tumors, which had previously been rarely considered for allogeneic HSCT.²²

Investigators at the National Cancer Institute (NCI) of the National Institutes of Health initiated a study to determine whether a clinically relevant GVT effect exists against metastatic breast cancer using allogeneic lymphocytes after reduced-intensity allogeneic HSCT. To differentiate potential antitumor effects of cytotoxic chemotherapy in a reduced-intensity conditioning regimen from the effects of allogeneic lymphocytes, the allogeneic stem-cell grafts were first T-cell depleted, and allogeneic lymphocytes were subsequently infused at set intervals remote from the time of chemotherapy administration. The following are the initial study results.

	PATIENTS AND METHODS

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Patient Eligibility
Patients with measurable metastatic breast cancer that had progressed after or failed to respond to prior therapy with an anthracycline and a taxane were eligible for this study. Patients were also required to have received at least one therapy for metastatic breast cancer. Patients whose tumors expressed estrogen and/or progesterone receptors or HER2-neu were required to have received prior therapy with a hormonal agent and trastuzumab, respectively. Patients with brain metastases were eligible if the brain metastases were treated and remained stable for a minimum of 4 weeks. All patients had a human leukocyte antigen–matched sibling who consented to serve as an allogeneic blood stem-cell donor. This study, CC 00-C-0119, was approved by the NCI institutional review board, and informed written consent was obtained from each patient and her respective donor.

Treatments
Patients initially received one to two cycles of an induction regimen consisting of cyclophosphamide (600 mg/m²/d) and fludarabine (30 mg/m²/d) concomitantly for 4 consecutive days (Fig 1). The purposes of the induction regimen were to deplete host immunity and to provide tumor control before transplantation. The induction regimen was administered in 21-day cycles. Patients received a maximum of two cycles of the induction regimen until the CD4⁺ count was below 50 cells/µL. This level of host CD4⁺ T-cell depletion was selected as it is associated with clinically significant immunosuppression and a reduced ability to reject allogeneic cells. If after one cycle of the induction regimen, the target CD4⁺ count was reached or there was radiographic evidence of disease progression, patients proceeded directly to transplant. All of the remaining patients proceeded to transplant after two cycles of the induction regimen, regardless of whether or not the target CD4⁺ count had been reached. Patients proceeded to transplantation within 2 weeks of completing (day 21) their final cycle of the induction regimen. Patients then received a conditioning regimen consisting of fludarabine (30 mg/m²/d) and cyclophosphamide (1,200 mg/m²/d) administered intravenously and concomitantly on days –6, –5, –4, and –3 prior to transplantation.

View larger version (31K): [in this window] [in a new window]   Fig 1. Treatment schema for patients participating on National Institutes of Health Clinical Center Protocol CC 00-C-0119. Cytoxan, cyclophosphamide; d, day; TCD, T-cell depletion; CsA, cyclosporine A; GVHD, graft-versus-host disease; DLI, donor lymphocyte infusions.

Starting on day +42 post-transplantation, patients were scheduled to receive dose-escalated, donor lymphocyte infusions (DLI). The DLI were scheduled for days +42, +70, and +98 post-transplantation, and contained 1 x 10⁶, 5 x 10⁶, and 1 x 10⁷ CD3⁺ cells/kg, respectively. The DLI were only administered if there was persistent disease and no evidence of GVHD. Patients were eligible to receive additional DLI beyond day +98, using the same criteria as the scheduled DLI. No additional therapy was permitted until 6 months after transplantation, with the exception of DLI.

Assessment of Response
Determinations of response were made by computed tomography (CT) scan after induction chemotherapy, at days +28, +42, +70, and +98 post-transplantation, and months +4, +5, +6, +9, and +12 post-transplantation. CT measurements were made independently by a National Institutes of Health Clinical Center radiologist (C.K.C.) not involved in patient care. A complete response was defined as complete resolution of all measurable and assessable disease for at least 28 days. A partial response was defined as a greater than 50% decrease in the sum of the products of the greatest (or longest) perpendicular dimensions of all measured lesions for at least 28 days, without evidence of new lesions. A minor response was defined as a greater than 25% but less than 50% decrease in all measured lesions for at least 28 days, without evidence of new lesions. Stable disease was defined as a less than 25% decrease or a no greater than 25% increase in all measured lesions for at least 28 days without evidence of new lesions. Progressive disease was defined as a greater than 25% increase in measured lesions or evidence of new lesions.

Adverse Events
Toxicities were defined using the NCI Common Toxicity Criteria Version 2.0. The severity of acute and chronic GVHD was graded according to Glucksberg criteria and International Bone Marrow Transplant Registry consensus criteria, respectively.^23,24

Assessment of Chimerism
Chimerism analysis was performed by the variable number tandem repeats–polymerase chain reaction method in a Clinical Laboratory Improvement Amendments–certified laboratory at the Blood Center of Southeastern Wisconsin. Chimerism was determined on total peripheral blood mononuclear cells every 2 weeks until 6 months post-transplantation, and then monthly thereafter. In addition, chimerism was determined intermittently post-transplant on samples enriched for T-lymphoid (CD3⁺) subsets. Lymphoid cell subset enrichment was performed by positive selection using either magnetic beads (Miltenyi Inc, Auburn, CA) or rosette technique (Stem Cell Technologies Inc, Vancouver, BC).

Statistical Analysis
The objective of this study was to determine if the administration of allogeneic lymphocytes remote from the chemotherapy in the transplant conditioning regimen would result in clinical responses in patients with advanced metastatic breast cancer. Since there was no prior experience as to what the response rate would be with this therapy, a predicted response rate of 30% was arbitrarily selected as a target, as similar response rates are observed with second-line chemotherapy in metastatic breast cancer patients who have received prior anthracyclines and taxanes.^4,25 The null hypothesis was that the rate of response in this group would be 10%, and the alternative hypothesis was that the response rate would be 30%. Using a one-tailed = .05, and with more than 80% power, it was estimated that 21 patients who engrafted after transplantation would provide an adequate sample size to reject the null hypothesis in favor of the alternative hypothesis.²⁶

Overall survival durations were calculated from transplant date until date of death or last follow-up. The probability of overall survival as a function of time was calculated using the Kaplan-Meier method.

	RESULTS

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Patient Characteristics
Twenty-two patients were enrolled onto the study between May 2000 and April 2003. Six patients did not proceed to transplantation; four patients experienced rapid disease progression before receiving any study therapy; one was found to have a second primary malignancy (ovarian adenocarcinoma); and one voluntarily withdrew. The median age of the 16 patients who underwent allogeneic HSCT was 43 years, and median times from original diagnosis and diagnosis of metastatic disease were 67 months and 24 months, respectively (Table 1). All patients had infiltrating ductal carcinoma. The median number of metastatic sites was three; the most common sites of metastatic disease were liver, lungs, and bone. All patients had received adjuvant chemotherapy. Five patients had previously received high-dose chemotherapy with an autologous HSCT. The median number of prior therapies they had received for metastatic disease was four.

Toxicities
All patients completed at least one cycle of induction chemotherapy without significant complication, with the exception of febrile neutropenia, which was documented in 37% of cycles administered. The most common post-transplantation complications was GVHD. Acute GVHD was observed in 10 patients. Nine patients required treatment with systemic corticosteroids for grade 2 to 4 acute GVHD, and eight of these nine had complete resolution of clinical GVHD. Four of 13 assessable patients developed chronic GVHD that was extensive in two cases. Other serious adverse events included one case of Epstein-Barr virus–associated lymphproliferative disorder, which completely resolved after planned discontinuation of cyclosporine and the first scheduled DLI. There was one case of Gram-negative sepsis, one case of systemic aspergillosis, and one case of congestive heart failure, which were all successfully treated. One patient died early post-transplantation (day +3) from multiorgan failure. One patient died 6 months after transplantation from hemorrhage during a thoracentesis procedure to drain a malignant pleural effusion.

DLI
Three patients did not receive any of the scheduled DLI, as they all had developed GVHD before day +42. Eight patients received all three scheduled DLI. Seven of these patients received additional DLI (range, four to 11) for persistent disease. Four patients received either one or two of the scheduled DLI. Three of these patients developed GVHD before their next scheduled DLI. The other patient experienced disease progression and physical decline requiring removal from study before next scheduled DLI.

Efficacy
Following induction chemotherapy, two patients were documented to have a partial response, three patients had a minor response, six patients had stable disease, and six patients had progressive disease as compared with measurements at study entry. Response determination at day +28 post-transplantation for the 15 surviving patients demonstrated that the conditioning regimen improved or stabilized disease in five and nine patients, respectively, and one patient experienced further progression. In sum, the induction chemotherapy and the conditioning regimen chemotherapy resulted in four partial responses and two minor responses at day +28 evaluation as compared with measurements at study entry.

Using the day +28 tumor measurements as a new baseline, six patients were subsequently observed to have tumor regression (Table 2). There were two partial responses and four minor responses among these six patients. These responses were observed 42 days to 13 months post-transplantation. The median duration of these six responses was 3 months (range, 1 to 7 months). One response occurred after planned cyclosporine taper (patient 12); the other five responses occurred after DLI. There were no responses among patients who were in a state of mixed T-lymphoid chimerism after day +42; all responses occurred after the establishment of complete donor T-lymphoid chimerism.

The case (patient 7) that best exemplifies these responses is outlined in Figure 2. At day +28 post-transplantation, the patient’s disease was stable, and donor T-lymphoid chimerism was below 30%. Subsequent planned DLI on days +42 and +70 increased overall donor chimerism to greater than 80%; however, she was documented to have new hepatic lesions and ascites on day +98 evaluation. On day +126 evaluation, regression in the patient’s liver lesion and ascites was observed. As she had no clinical evidence of GVHD and persistent disease, an additional DLI was given. The patient subsequently experienced an approximate 90% reduction in liver metastases as compared with day +70 measurements when she was noted to have progressive disease. At approximately 6 months post-transplantation, she developed GVHD of the skin and gastrointestinal tract that required treatment with systemic corticosteroids. She was subsequently documented to have progressive disease at 8 months post-transplantation. Similarly, in four of the other five patients, tumor regression occurred before the onset of clinical GVHD, and tumor progression occurred within 2 months of starting systemic corticosteroid administration for treatment of GVHD. One response occurred without clinical evidence of GVHD.

View larger version (25K): [in this window] [in a new window]   Fig 2. Representative clinical course of a patient (patient 7) who responded to adoptive cellular therapy with allogeneic lymphocytes after allogeneic hematopoietic stem-cell transplantation. DLI, donor lymphocyte infusions. Whole-blood and lymphoid (CD3) chimerism was determined by the variable number tandem repeats–polymerase chain reaction method.

Overall, six partial responses and four minor responses were observed among the sixteen patients who underwent transplantation. Using the most conservative evaluation, with 16 total patients, six responses (37.5%) have an associated lower bound of a one-sided 95% CI of 17.8%. Based on 15 patients, who survived beyond day +14 with engraftment of donor cells, the six responses (27%) have an associated lower 95% confidence bound of 19.1%. In either case, an approximately 35% to 40% partial response rate was obtained, and there is statistical evidence to reject the 10% null rate. In addition to the two patient deaths described above, there have been 10 additional deaths, all with progressive disease. For all 16 patients who underwent allogeneic HSCT, the median overall survival from time of transplant was 10.3 months, at a median potential follow-up of 23.4 months.

	DISCUSSION

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In this group of 16 patients with advanced metastatic breast cancer, six patients had tumor regression at a time that was remote from potential antitumor effects of cytotoxic chemotherapy in the transplant conditioning regimen. The possibility that these regressions were delayed responses to the cytotoxic effects of the conditioning regimen seems unlikely, as five of the regressions occurred at day +70 or beyond, and the other patient had experienced disease progression after the induction regimen. These results strongly suggest that tumor regression was associated with an immune-mediated reaction related to allogeneic HSCT. The precise mechanism of this immune response cannot be determined as to whether responses were tumor specific or secondary to general alloreactivity. Responses were observed in a minority of patients, were of relatively short duration, and seemed to be quickly abrogated with the administration of systemic immunosuppression. Despite these limitations, these observations provide impetus for the further development of allogeneic cellular therapy in specific, and immunotherapy in general, as therapies for breast cancer.

Breast cancer is not considered to be particularly immunogenic. Very few tumor antigens that are specific to breast cancer have been identified. Rather, a large number of "self" antigens are overexpressed on breast cancer cells.^27,28 These overexpressed self antigens include CEA, MUC-1, p53, and MAGE-3, and they are capable of generating both antibody and cytotoxic T-cell responses in humans.^10,29 Despite clinical evidence that immunologic responses can be generated against breast cancer, significant clinical responses have not been observed with various forms of immunotherapy.¹² The results from this study strongly suggest that allogeneic lymphocytes are capable of generating sufficient reactivity to result in clinical responses against breast cancer.

The successful application of adoptive cellular therapy has been limited primarily to renal-cell carcinoma and melanoma, two solid tumors which are susceptible to other immunotherapies, such as interferon and interleukin-2. The resistance of breast cancer and other solid tumors to these and other immunotherapies has been attributed to multiple factors, including the immunosuppressive microenvironment of the tumor, an incompetent immune system, and excessive tumor burden. These barriers have directed immunotherapeutic strategies toward the adjuvant and preventive clinical settings, and away from grossly metastatic disease. These results suggest that these barriers may partially be overcome using allogeneic HSCT as a treatment platform.

The responses in this study were often delayed, which may reflect the necessity to establish complete donor lymphoid chimerism for an optimal immunologic response. In the interim, there was often tumor progression. However, conventional therapies, such as hormonal agents and trastuzumab, could potentially be incorporated into this approach to provide disease control until an optimal immunologic effect occurs. Additionally, selected chemotherapeutic agents could provide disease control and theoretically enhance an immune-mediated response from allogeneic cellular therapy in a multimodality approach to metastatic breast cancer.³⁰

The results of this study should be interpreted cautiously. We do not intend for these data to be interpreted as stating that allogeneic HSCT, in its current form, is a beneficial treatment option for patients with advanced metastatic breast cancer. There was significant morbidity associated with this treatment in the forms of GVHD and infection, and the observed responses did not necessarily correlate with a survival advantage, though the latter was not a specific aim of the trial. GVHD presents a formidable investigational challenge, as its presence was associated with tumor regression, yet its treatment with systemic corticosteroids was associated with an abrogation of response. The observations of late tumor regressions in this trial suggest that immune-mediated responses against breast cancer are possible. The clinical question that remains is how to optimally and safely exploit the responses seen with allogeneic cellular therapy for metastatic breast cancer in the context of currently available treatments.

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted January 22, 2004; accepted April 21, 2004.

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