AUTOIMMUNE ADDISON’S DISEASE AFTER TREATMENT WITH INTERLEUKIN-2 AND TUMOR-INFILTRATING LYMPHOCYTES
Jennifer S. Wahle, M.D., John P. Hanson, M.D., Joseph L. Shaker, M.D., James W. Findling, M.D.
ABSTRACT
Autoimmune thyroiditis with hypothyroidism is a well-known complication of immunotherapy with inter- leukin-2 (IL-2) with or without lymphokine-activated killer (LAK) cells. To date, however, no cases of IL- 2/LAK-induced autoimmune adrenalitis with adrenal insufficiency have been reported. We describe a patient who developed primary adrenal insufficiency following IL-2/tumor-infiltrating lymphocytes (TIL) immunothera- py for renal cell carcinoma. A 64-year-old male with renal cell carcinoma metastatic to bone, skin, lung, and the central nervous system presented for IL-2/TIL treatment. Nine months earlier, he had undergone a right nephrecto- my and adrenalectomy. He had already received two courses of IL-2 and one course of IL-4 following surgery. Dynamic studies of adrenal function performed prior to IL-2/TIL immunotherapy demonstrated intact cortisol and aldosterone responses to ACTH as well as negative adrenal antibodies. One week after IL-2/TIL therapy, the patient developed a nonanion gap metabolic acidosis, hypotension and hypoglycemia. Adrenocortical function was re-evaluated demonstrating blunted cortisol and aldosterone responses to ACTH with an elevated plasma ACTH confirming the presence of primary adrenal insuf- ficiency. Adrenal antibodies were now positive. Hydrocortisone and fludrocortisone were given with a good clinical response. We suggest immunotherapy with IL-2/TIL may cause adrenal insufficiency by activating autoimmune adrenalitis.
INTRODUCTION
Interleukin-2 (IL-2) is a potent cytokine produced by helper T-cells in response to an immunologic stimulus. First described in 1976 by Morgan and associates (1), IL- 2 has been found to stimulate T-cell proliferation, enhance natural killer cell function, and induce the formation of cells, termed lymphokine-activated killer (LAK) cells, from the null cell population of lymphocytes (1,2). LAK cells demonstrate lytic activity for fresh, autologous, or syngeneic tumor cells but not for normal cells (2,3).
IL-2 has also been shown to stimulate the prolifera- tion of cells, termed tumor-infiltrating lymphocytes (TIL’s), found within the tumor itself. These cells are in fact cytotoxic T-cells which have the specificity to kill only the cells of the tumors from which they are derived and no others (4). The selective destruction of tumor cells
Submitted for publication January 18, 1994
Accepted for publication in final form May 3, 1994
Departments of Medicine of Medical College of Wisconsin and of St.
Luke’s Medical Center,Milwaukee, WI
Reprint requests to Dr. Findling, Department of Medicine, St. Luke’s Medical Center, HS Suite #503, 2901 West Kinnickinnic Avenue, Milwau- kee, WI 53215
Copyright @ 1995 AACE.
without untoward effects on normal cells provides the ideal therapy for cancer.
Adoptive immunotherapy using high doses of IL-2 with or without LAK cells or TIL’s has been shown to induce tumor regression in a number of malignancies. Response rates have been particularly encouraging in patients with melanoma or renal cell carcinoma (2,3,5,6). Unfortunately, significant dose-related toxicity can result from the administration of IL-2 (2,3,7). Well-known toxic effects include transient fever and chills, weight gain, hypotension, azotemia, interstitial pulmonary edema, hyperbilirubinemia, hematopoietic suppression, and neu- ropsychiatric disturbances (2,3,5,8,9).
Hypothyroidism following immunotherapy with IL-2 with or without LAK cells has been described in a number of cases (10,11,12). The development of thyroid abnor- malities is often associated with the production of thyroid autoantibodies and thus thought to be the result of exacer- bation of preexisting autoimmune thyroiditis (10,11,12). Autoimmunity need not be restricted to the thyroid gland, however, and here we describe a patient who developed primary adrenal insufficiency following IL-2/TIL immunotherapy for renal cell carcinoma. The presence of adrenal autoantibodies in our patient suggests that activa- tion of autoimmune adrenalitis was the most likely cause of his hypoadrenalism.
CASE REPORT
A 64-year-old white male was admitted in January 1991 for pain management and consideration of IL-2/TIL immunotherapy for metastatic renal cell carcinoma. He had initially been diagnosed with metastatic renal cell car- cinoma in December 1989 after presenting with left hip pain. A right kidney mass with extension into the right adrenal gland and extensive bony metastases were found. He subsequently underwent a right nephrectomy and right adrenalectomy in March 1990. This was followed by two courses of IL-2 therapy in May 1990 and one course of IL- 4 therapy in October 1990. The patient also received radi- ation therapy to the spine, pelvis, right femur, right humerus, and right scapula as part of his pain manage- ment.
On presentation in January 1991, the patient now had extensive metastatic disease involving the bones, skin, lungs, and central nervous system. He had no history of thyroid disease, diabetes mellitus, or adrenal insufficien- cy. He was not taking any medications known to alter adrenocortical function. His mother was known to have a goiter, but there were no other known endocrinopathies in the family. On admission the thyroid was not palpable, and he had no clinical signs of adrenal insufficiency. He had a performance status of 2 (World Health Organi- zation).
Despite a 2.5 x 2.0 cm focal enlargement of the left adrenal gland found on CT scan (Figure 1), initial dynam- ic studies of adrenocortical function were normal (Table 1). Adrenal autoantibodies, measured retrospectively, were negative (Immunofluorescent assay, Nichols Institute, San Juan Capistrano, California). Initial labora- tory tests of thyroid function demonstrated mild hypothy- roidism with a serum thyroxine concentration (T4) of 5.8 ug/dL (Normal: 5.2-11.0), a triiodothyronine resin uptake (T3RU) of 43% (Normal: 35-45), and a serum thyrotropin concentration (TSH) of 9.5 mU/L (Normal: 0.4-5.0). The patient was started on levothyroxine, 50 µg/day. The serum antithyroglobulin and antimicrosomal antibodies were negative.
Chemotherapy consisting of 50 mg/kg cyclophos- phamide was given on day 1. Immunotherapy with IL- 2/TIL was started on day 2. The regimen consisted of a 20 minute infusion of TIL cells for three days at 10 x 1010 cells/dose concurrent with 15 minute infusions of IL-2 every eight hours for seven days at 4.62 mmU/dose. Supportive therapy consisted of acetominophen, indomethacin and meperidine to relieve fever and chills during IL-2/TIL infusion.
Side effects of the immunotherapy included fever, fluid retention, pancytopenia and mild hypotension. On the sixth day of therapy, following the final infusion of IL- 2, the patient developed a nonanion gap metabolic acido- sis (sodium 138 mmol/L, potassium 4.2 mmol/L, chloride 108 mmol/L, bicarbonate 18 mmol/L), worsening hypotension (systolic blood pressure 70 mmHg) and hypoglycemia (capillary glucose 43 mg/dL). Supportive treatment was administered consisting of dextrose-con- taining intravenous fluids, plasmanate and a neosynephrine infusion. Adrenal insufficiency was sus-
pected and, following re-evaluation of adrenal function, the patient was started on hydrocortisone and fludrocorti- sone. Clinical adrenocortical insufficiency was now evi- dent with a plasma ACTH of 181 pg/mL and blunted cor- tisol and aldosterone responses to ACTH (Table 1). Adrenal autoantibody titers were now positive at 1:2 titer. Repeat CT scan of the adrenal gland demonstrated no change in the size of the mass. The patient had a good clinical response to steroid therapy with increased blood pressure as well as resolution of both his nonanion gap metabolic acidosis and his fever. The patient’s renal cell carcinoma progressed and he expired five months later. A post-mortem examination was not performed.
DISCUSSION
We have described the development of clinically sig- nificant adrenocortical insufficiency following immunotherapy with IL-2/TIL’s for metastatic renal cell carcinoma. The exact mechanism for the hypoadrenalism is not certain. However, the association of the adrenal insufficiency with the interim appearance of antiadrenal antibodies makes an autoimmune mechanism most likely.
IL-2 has a number of immunologic effects. Cytokines such as IL-2 have actually been shown to acti- vate the pituitary-adrenal axis thus increasing the recogni- tion of an interaction between the immune and neuroen- docrine systems (13). In susceptible patients immunother- apy for melanoma or renal cell carcinoma may induce autoimmune thyroid disease (2,3,5,14). Similarly, we propose that immunotherapy with IL-2/TIL’s may cause adrenal insufficiency by activating autoimmune adrenali- tis.
Susceptibility to autoimmune thyroid and adrenal dis-
ease has been linked to certain Class II, HLA-DR, anti- gens (15,16). Normally the expression of these antigens is restricted to B-lymphocytes, macrophages, dendritic and other antigen-presenting cells, and capillary endothelium (17,18). However, human thyroid follicular cells have been found to express Class II HLA antigens in autoim- mune thyroid disease (17,18).
HLA-DR expression on follicular thyroid cells can be induced experimentally by plant lectins (19) and recombi- nant interferon gamma (20). IL-2 -induced synthesis of interferon gamma may therefore lead to expression of DR antigens. This aberrant expression of HLA antigens by thyroid epithelial cells can then lead to presentation of these autoantigens to T-lymphocytes. This causes activa- tion of the T-lymphocytes and the subsequent develop- ment of autoimmune disease (20). Autoimmunity need
TABLE 1 Rapid ACTH Stimulation Test
PRE - IL-2/TIL Rx (12/6/90)
POST - IL-2/TIL Rx (1/23/91)
| Basal | +30 minutes | Basal | +30 minutes | |
|---|---|---|---|---|
| ACTH | ||||
| (pg/mL) | 38 | - | 181 | - |
| Cortisol | ||||
| (µg/dL) | 20 | 25 | 12 | 15 |
| PRA | ||||
| (ng/ml/hr) 1.3 | - | 0.2 | - | |
| Aldosterone | 28 | |||
| (ng/dL) 21 | 1 | 2 | ||
* After basal levels drawn, 250 µg cosyntropin adminis- tered intravenously.
TABLE 1: Normal ranges are as follows: ACTH 9-52 pg/ml; Cortisol 6-22 µg/dl; PRA 1.4-2.8 ng/ml/hr; Aldosterone 2-9 ng/dl. The normal peak cortisol and aldosterone response to cosyntropin are 18 µg/dl and 18 ng/dl, respectively.
not be restricted to the thyroid gland, however, and this pathogenetic mechanism could be applicable to other autoimmune disorders. IL-2/LAK-cell immunotherapy has been reported to cause vitiligo and exacerbate cuta- neous vasculitis (10). Our patient had biochemical evi- dence of primary hypothyroidism after IL-2 and IL-4 immunotherapy alone suggesting that he was at increased risk for other autoimmune endocrinopathies. Our patient had normal adrenocortical function and negative adrenal autoantibodies prior to IL2/TIL immunotherapy. The appearance of adrenal autoantibodies associated with clin- ical and biochemical evidence of primary adrenal insuffi- ciency suggests that the immunotherapy in this patient activated autoimmune adrenalitis in a manner similar to the well appreciated IL2 activation of autoimmune thyroid disease. Although the adrenal autoantibody titre in our patient was relatively low, its presence implicates an autoimmune mechanism since the measurement of anti- adrenal antibodies has good specificity for autoimmune
Addison’s disease (21).
Although an autoimmune mechanism may be the most likely explanation for adrenal insufficiency in our patient, several other factors deserve consideration. Metastatic disease is very likely as evidenced by the focal enlargement of the adrenal gland seen on CT scan. Metastases could contribute to adrenal insufficiency by two mechanisms. First, direct invasion of the adrenal tis- sue by tumor cells causes destruction of normal adrenal cells and decreased adrenocortical reserve. Second, as IL- 2/TIL cells are directed against tumor cells, destruction of the adrenal cortex could result as IL-2/TIL cells attack the metastatic disease within the gland itself.
The decrease in functional adrenocortical reserve resulting from metastatic disease may have placed our patient at increased risk for the development of clinically significant adrenal insufficiency from adrenalitis. Since hypothyroidism may decrease the metabolic clearance of cortisol, the initiation of thyroid hormone replacement in our patient may have served to precipitate adrenal crisis.
Adrenal hemorrhage subsequent to IL-2 therapy with resultant insufficiency is also a possibility as described by VanderMolen, et al (22). They propose that the hemody- namic and hormonal effects of IL-2, i.e. shock-like state, increased plasma ACTH, cortisol, epinephrine and norep- inephrine, predisposes patients to adrenal hemorrhage. This was unlikely to have occurred in our patient, howev- er, without a significant change in the size of the gland or CT evidence of hemorrhage.
In summary, clinically significant primary adrenal insufficiency may be an important and potentially serious complication of IL-2/TIL therapy. This report suggests that this phenomenon may result from activation of autoimmune Addison’s disease.
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