Antitumor Activity in Melanoma and Anti-Self Responses in a Phase I Trial With the Anti-Cytotoxic T Lymphocyte–Associated Antigen 4 Monoclonal Antibody CP-675,206
Cytotoxic T lymphocyte–associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans. A phase I trial was conducted to test the safety of CP-675,206.
Patients and Methods
Thirty-nine patients with solid malignancies (melanoma, n = 34; renal cell, n = 4; colon, n = 1) received an intravenous (IV) infusion of CP-675,206 at seven dose levels. The primary objective was to determine the maximum-tolerated dose and the recommended phase II dose.
Results
Dose-limiting toxicities and autoimmune phenomena included diarrhea, dermatitis, vitiligo, panhypopituitarism and hyperthyroidism. Two patients experienced complete responses (maintained for 34+ and 25+ months), and there were two partial responses (26+ and 25+ months) among 29 patients with measurable melanoma. There have been no relapses thus far after objective response to therapy. Four other patients had stable disease at end of study evaluation (16, 7, 7, and 4 months). Additionally, five patients had extended periods without disease progression (36+, 35+, 26+, 24+, and 23+ months) after local treatment of progressive metastases. Longer systemic exposure to CP-675,206 achieved in higher dose cohorts predicted for a higher probability of response.
Conclusion
CP-675,206 can be administered safely to humans as a single IV dose up to 15 mg/kg, resulting in breaking of peripheral immune tolerance to self-tissues and antitumor activity in melanoma.
Introduction
Evidence from experimental carcinogenesis models demonstrates that tumors develop more frequently in immune-suppressed hosts, incriminating a central role of immune surveillance in the pathogenesis of cancer.1 Likewise, human subjects with congenital or acquired immune suppression have an increased frequency of cancer (for review, see Dunn et al2). However, these antitumor immune protective mechanisms ultimately fail to control tumor growth adequately in patients with progressive cancer. Immune failure may be due to tumor-induced immune escape or immune system homeostatic negative regulatory pathways. Blockade of mechanisms of immune system negative regulation may result in tumor regression by boosting the natural immune response against cancer.3
CTLA4 (CD152) is an activation-induced, type I transmembrane protein expressed by T lymphocytes and monocytes3-5 that functions as an inhibitory receptor for the costimulatory molecules B7.1 (CD80) and B7.2 (CD86). In resting T lymphocytes, B7 molecules are recognized by the activating receptor CD28, a molecule constitutively expressed on the surface of T lymphocytes. B7/CD28 interactions provide the second signal for T-cell activation, after antigen recognition has taken place through the interaction of major histocompatibility complex (MHC) and T-cell receptors (TCRs). After activation, T cells upregulate CTLA4, which successfully competes for binding to B7 molecules, due to a much higher binding affinity. Cross linking of CTLA4 by B7 in the context of TCR engagement inhibits TCR signaling, IL-2 gene transcription and T-cell proliferation.3,4 In addition, CD4+ CD25+ T-regulatory (T-reg) cells constitutively expressing CTLA4 provide reverse signaling through B7 costimulatory molecules directly to T cells,6 or indirectly through dendritic cells (DCs).7,8 CTLA4/B7 interaction results in the induction of indolamine 2,3 dioxygenase (IDO) in a subset of DCs, a rate-limiting enzyme on tryptophan catabolism.7 IDO-expressing DCs acquire potent and dominant T cell–suppressive properties.9 The critical inhibitory role of CTLA4 on T-cell homeostasis and maintenance of peripheral self-tolerance is clearly exemplified by the lethal lymphoproliferation and autoimmunity in CTLA4 gene knock-out mice.10,11
CP-675,206 is a fully human IgG2 monoclonal antibody with high CTLA4 specificity. CP-675,206 antagonizes the binding of CTLA4 to B7 ligands resulting in enhanced T-cell activation, as demonstrated by increased cytokine production tested in in vitro assays.12 Original work conducted primarily by Allison's group demonstrated that CTLA4 blocking antibodies induced rejection of established tumors and immunologic memory in murine models.3,4 In nonhuman primates, anti-CTLA4 antibodies enhanced T-cell and antibody responses to an infectious-disease vaccine and a whole tumor cell vaccine.13 Three prior studies testing the safety and antitumor activity of a different anti-CTLA4 monoclonal antibody have been published.14-16 These studies attest to the biologic and clinical activity of this class of agents. We herein present the results of a single intravenous (IV) infusion, dose-escalation, phase I clinical trial demonstrating that CP-675,206 can be administered safely at doses that result in immune activation against self-tissues and objective antitumor responses in patients with melanoma.
Patients and Methods
Trial Objectives
Thirty-nine patients with solid malignancies were enrolled between January 2002 and August 2003 at the University of California, Los Angeles (Los Angeles, CA) and M.D. Anderson Cancer Center (Houston, TX). This was the first-in-human, open label, phase I dose-escalation study of a single, IV infusion of CP-675,206. The protocol and consent forms, and all modifications, were approved by the local institutional review boards (IRBs). The M.D. Anderson Cancer Center IRB allowed only patients with advanced and measurable disease to participate; all other parameters were common to both study sites. The primary objective was to determine the maximum-tolerated dose (MTD) and the recommended phase II dose. Secondary objectives were to evaluate safety, tolerability, pharmacokinetics (PK), and antitumor activity of CP-675,206.
Study Design and Drug Administration
A modified Fibonacci dose escalation design was used. At least three patients per cohort were enrolled, with further patients enrolled in case of dose-limiting toxicity (DLT) or to further define the effects of CP-675,206. The starting dose of 0.01 mg/kg was chosen because of theoretical concerns of inducing cytokine release syndrome.17-19 DLT was defined as any treatment-related toxicity ≥ grade 3 according to the National Cancer Institute Common Toxicity Criteria version 2.0.20 Cohorts receiving doses greater than 1 mg/kg were monitored for subacute autoimmune phenomena for 6 to 8 weeks before enrolling patients at the next dose level. CP-675,206 was supplied by Pfizer Inc (Groton, CT) as a liquid solution in vials containing 25 mg/5 mL, and was administered intravenously at a clinical research center.
Redosing
Patients in the first three cohorts were allowed to re-enter at higher dose levels (added to the minimum of at least three new patients in that cohort) after they had completed their study follow-up period in the absence of unacceptable toxicity. Additionally, separate protocols and investigator new drug applications (IND) were submitted from each investigational site to allow redosing of patients who received clinical benefit from the initial single dose.
Eligibility Criteria
Patients with solid malignancies, with no restriction in histology, and either (1) with metastatic cancer, with or without measurable lesions and irrespective of prior treatment; or (2) in the adjuvant setting, after completely resected cancer but at high risk of recurrence (> 50%); in both cases, prior therapy should have been completed at least 4 weeks before enrollment. Other eligibility criteria included an estimated life expectancy > 6 months and adequate bone marrow, hepatic and renal function. Patients were excluded if they had a personal history of or significant evidence of risk for chronic inflammatory or autoimmune disease, required systemic corticosteroids, had history of chronic colitis, or had active brain metastasis. During the course of the study, bronchial asthma was added to the exclusion criteria based on data associating this condition with a polymorphism in the CTLA4 gene.21
Study Procedures
Screening included hematology, chemistry, coagulation, autoantibody panel, hepatitis serologies, T3, T4, thyroid-stimulating hormone, lipase, amylase, fecal occult blood, urine analysis and ECG. Plasma levels of tumor necrosis factor (TNF-) α, interleukin-6 (IL-6), and sTNF-RII were determined in peripheral blood by enzyme-linked immunosorbent assay (ELISA; R&D Systems, Minneapolis, MN). Plasma samples for PK were collected at 12 time points. Samples were analyzed by ELISA using recombinant huCTLA4/murine immunoglobulin (Ig) as capture and a rat antihuman IgG–horseradish peroxidase as secondary antibody. Circulating human antihuman antibodies (HAHA) were analyzed by an immunoassay using F(ab′)2 fragments as capture ligands; neutralizing HAHA were assayed in a huCTLA4/muIg competition assay.
Criteria for Tumor Response
Patients who received the study drug and had measurable disease assessed at baseline and at least once on-study were considered assessable for response. The WHO criteria were used to evaluate response to therapy.22 Non–previously irradiated lesions that could be accurately measured in two perpendicular dimensions with a minimum size of 2.0 cm × 2.0 cm with conventional techniques, or 1.0 cm × 1.0 cm with spiral computed tomography scan, were considered measurable lesions.
Statistical Analysis
The noncompartmental PK analysis was performed using WinNonlin Enterprise, version 3.2 (Pharsight Corp, Mountain View, CA). The PK/pharmacodymanic (PD) analysis was performed using S-PLUS 2000 Professional (Release 3; Mathsoft, Cambridge, MA). Efficacy data were fit to the following logistic model of drug action by maximum likelihood regression:
where exposure is systemic exposure to CP-675,206. The parameter CONS determines the probability of the event occurring without exposure to CP-675,206 and the parameter COEF determines the change in the probability of an event given exposure to CP-675,206. The statistical significance of the COEF estimates was assessed by analysis of deviance.23
Results
Patient Characteristics
Thirty-nine patients were enrolled between January 2002 and August 2003. This trial had broad subject eligibility, allowing inclusion of patients with resected tumors at high risk of relapse and patients with metastatic disease regardless of prior therapy (see Patients and Methods). The rationale was that the assessment of the trial primary end points (ie, toxicity and immune activation) could be fulfilled with patients regardless of the presence of measurable disease. As the trial progressed, the study investigators focused on enrolling patients with measurable metastatic melanoma, which was hypothesized to be a tumor type more likely to show demonstrable benefit from this immunologic intervention. CP-675,206 was administered to four patients (10%) in the adjuvant setting, to 11 (28%) as front-line therapy for metastatic disease, and to 24 (62%) as second or greater line of therapy for metastatic disease (Table 1
Table 1. Patient Characteristics
Characteristic
No.
%
No. of patients
39
Sex
Male
27
69
Female
12
31
Age, years
Median
54
Range
30–78
Tumor types and stage
Melanoma
III NED
1
III MD
1
IV NED
3
IV NMD
2
IV MD
27
69
RCC IV MD
4
Colon IV MD
1
Sites of metastasis
Skin
6
SC tissues
9
Lymph nodes
19
Lung
23
Liver
9
Adrenal gland
3
Kidney
2
Bone
3
Serosal effusion
1
Intestine
1
Pancreas
1
Prior treatment
Surgery only
2
Radiation therapy
15
Chemotherapy
18
Cytokine therapy
26
Other immunotherapy
15
Abbreviations: NED, no evidence of disease; MD, measurable disease; NMD, non-measurable disease; RCC, renal cell carcinoma; SC, subcutaneous.
). Most had melanoma (34 patients, 87%). Twenty-eight (80%) of 35 patients with metastatic disease had visceral metastasis.
Toxicity
Three of six patients at 15 mg/kg experienced DLTs (Table 2
Table 2. Toxicities Felt to Be at Least Possibly Related to CP-675,206 Administration
). Therefore, the immediately lower dose level, 10 mg/kg, was considered the MTD. The DLTs were dermatitis and diarrhea. Dermatitis presented most often as a pruriginous maculopapular erythema, typically developing within 2 weeks from dosing and lasting for less than 1 month (Figs 1A and 1B
Fig 1. Toxic events during CP-675,206 administration. (A) Patchy dermatitis in a patient treated with CP-675,206 at 3 mg/kg. (B) Generalized dermatitis in a patient dosed at 6 mg/kg. (C and D) Lymphocytic colitis in a patient treated with CP-675,206 at 15 mg/kg. Magnetic resonance imaging of the brain on patient 11, who had evidence of decrease in the level of hypophyseal hormones concomitant with radiographic evidence of swelling of the hypophysis (E) predose, (F) 3+ months, and (G) 8+ months.
). In one patient, biopsy of active skin lesions revealed a perivascular lymphocytic and eosinophilic infiltrate. Diarrhea was watery without blood or leukocytes, and also typically presented within 2 weeks and lasted 2 to 3 weeks. Two patients with grade 3 diarrhea (patient 115 at 6 mg/kg, and patient 12 at 15 mg/kg) underwent colonic biopsies, one of them revealing intraepithelial lymphocytic infiltrates consistent with lymphocytic colitis (Fig 1C) and the other without evidence of these infiltrates. A patient dosed at 1.0 mg/kg had reactivation of Clostridium difficile colitis in the setting of a prior history of relapsing infectious colitis triggered by antibiotic therapy, but no prior events for more than 6 months before CP-675,206 dosing. This patient was eligible for redosing, and the diarrhea reappeared after redosing at 6 mg/kg, this second time being C difficile negative. All other cases of diarrhea were C difficile negative. Several patients at the highest dose cohorts developed asymptomatic elevations of amylase, lipase, and liver enzymes. Two patients had worsening of pre-existing vitiligo and one developed de novo vitiligo. One patient developed panhypopituitarism, which spontaneously resolved over the next 3 months (Fig 1D). One patient developed asymptomatic autoimmune thyroiditis with elevated antithyroglobin and anti–thyroid peroxidase antibodies, which normalized within 1 month. The patient later developed hypothyroidism requiring chronic replacement therapy. With the exception of hypothyroidism and vitiligo, toxicities resolved within weeks without corticosteroids or other immune suppressants. Neither the cytokine release syndrome nor hypersensitivity reactions were observed.
Clinical Outcome
Four patients with melanoma experienced objective antitumor responses (Table 3
Table 3. Clinical Characteristics of Patients With Melanoma Who Received Apparent Clinical Benefit From CP-675,206
Patient Study Code Number
Sex
Age (years)
Prior Tx
Sites of Disease
Dose
Response
Redose
Post-Tx
Current Status
OS (months)
102/119
Female
54
SX IFN-α2b IL-2 + histamine MART-1/DC vaccine
LN, lung
0.01/6.0
SD PFS, 16 months
Y
CTLA4 redose AdVMART1/DC SX to brain met
AWD
38+
108
Female
50
XRT SX
Bone
1.0
PD
Y
CP-675,206 redose SX to LN met
NED
36+
110
Male
50
IFN-α2b combination chemo XRT to brain met SX to lung met
Abbreviations: Tx, treatment; OS, overall survival; PFS, progression-free survival; SX, surgery, IFN, interferon; IL-2, interleukin-2; MART1/DC, MART-127-35 peptide-pulsed dendritic cells; AdVMART1/DC, MART-1 genetically-modified dendritic cells using an adenoviral vector; XRT, radiation therapy; chemo, chemotherapy; biochemo, biochemotherapy; met, metastasis; alk phos, alkaline phosphatase; GGT, gamma glutamyl transferase; PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response; NA, not assessable due to lack of lesions fulfilling the criteria of measurable disease; Y, yes; N, no; LN, lymph node; SC, subcutaneous; RFA, radiofrequency ablation; NED, no evidence of disease; AWD, alive with disease.
). Patient 113 (3 mg/kg) had residual (biopsy-proven) melanoma metastatic to the lungs after therapy with a MART-1 peptide-pulsed DC vaccine approximately 1 year earlier, and two doses of another CTLA4 blocking monoclonal antibody, the last one 6 months before receiving CP-675,206. This patient has been recently reported within a cohort of 10 patients receiving a MART-1 peptide–ulsed DC vaccine.24 The patient underwent an open–lung biopsy before participating in the current trial, which revealed the presence of a lung mass with active melanoma. She attained a complete response (CR) after dosing with CP-675,206, and is currently receiving maintenance with CP-675,206. Patient 125 (10 mg/kg) had progressive malignant melanoma to the skin, lung, liver and peritoneum after biochemotherapy and attained a partial response (PR; Fig 2A
Fig 2. Examples of tumor responses. Computed tomography (CT) scans of the abdomen in patient 125 treated with CP675,206 at 10 mg/kg (A) before CP-657,206, (B) 4 months later, and (C) 14 months later. CT scans of the chest in patient 13 treated with CP675,206 at 15 mg/kg (D) before CP-657,206, (E) 3 months later, and (F) 13 months later. Imaging studies on patient 14 treated with CP675,206 at 15 mg/kg, with evidence of increase in size of a chest wall mass (G) before CP-657,206, (H) 3 months later, and (I) 12 months later. Histopathologic evaluation of the chest wall mass resected from patient 14, with evidence of a marked inflammatory response in the resected lesion clinically labeled as progressing to therapy (J) hematoxylin and eosin stained and (K) CD15.
). He is currently receiving CP-675,206 maintenance with residual small lung lesions at 26+ months. Patient 12 (15 mg/kg) had decrease in size in lung metastasis labeled as stable disease (SD) at the end of study (day +90), and eventually evolved to have criteria of a PR at 18 months from dosing. This patient continues in PR at 25+ months with two subsequent doses of CP-675,206. Patient 13 (15 mg/kg) had metastatic disease in the lung and experienced a CR. He remains free of disease at 25+ months without further therapy (Fig 2B).
Four patients were classified as having SD as best overall response (patient 102/119, 0.01 mg/kg and 3 mg/kg redosing; patient 110, 3 mg/kg; patient 120, 6 mg/kg; patient 128, 10 mg/kg). Two of these patients had stabilization of lung metastases and two of soft tissue disease (lymph node and subcutaneous tissue) ranging from 4 to 16 months (Table 3). In addition, patient 126 (15 mg/kg) entered the study after surgical resection of a large thoracic tumor, with positive margins of resection and residual bilateral pulmonary subcentimeter nodularities. This patient did not meet criteria of measurable disease and her tumor response could not be assessed, but she did experience 16 months without apparent disease progression. She has since developed brain metastases, treated with irradiation and temozolomide plus thalidomide.
Five patients classified as having SD or progressive disease (PD) at end of study evaluation underwent surgical resection of residual lesions, which was followed with long periods of disease-free survival. Patient 108, originally dosed at 1.0 mg/kg, had metastatic mucosal melanoma to the bone and received redosing at 6.0 mg/kg. This patient developed a submandibular nodal tumor recurrence. After complete resection of this node, the patient continues to be alive and currently without evidence of disease after complete resolution of bone lesions (evaluated by bone scan, positron emission tomography and magnetic resonance imaging) at 36+ months. Patient 110 (3 mg/kg) had a history of resected brain and lung metastasis, and entered the trial with progressive subcutaneous metastasis. This patient had progression after CP-675,206 and a subsequent DC-based vaccine trial. The two metastatic sites were later resected and the patient continues to be alive with no evidence of disease (NED) at 35+ months. Patient 11 (15 mg/kg) had progression of liver metastasis and underwent complete surgical resection followed by a multipeptide vaccine, and remains without relapse at 26+ months. Patient 127 (15 mg/kg) had a solitary liver lesion and developed progressive small bowel metastasis after dosing. The bowel metastases were resected and the liver lesion underwent radiofrequency ablation; the patient remains without relapse at 24+ months. Patient 14 had regression of multiple lung metastases but increase in the size of a single chest wall lesion, which was resected at the end of study follow-up (Fig 2C). Surgical resection of the residual mass demonstrated an extensive infiltrate of macrophages within and around areas of tumor necrosis. This was labeled as PD by radiologic size criteria, but may very well reflect a misclassification of the response based on imaging of an ongoing inflammatory response. This patient continues without relapse at 23+ months.
PK
CP-675,206 exhibits a biphasic PK profile following IV infusion (Fig 3A
Fig 3. Pharmacokinetic analysis of CP-675,206 after administration to human subjects. (A) Mean plasma CP-675,206 concentrations over time following a single intravenous dose of CP-675,206. (B) Logistic model fit of the relationship between efficacy, measured as clinical benefit response (complete response, partial response, stable disease, and patient 14) and CP-675,206 systemic exposure, measured as the plasma concentration of CP-675,206 4 weeks postdosing (C4 week). (C) CP-675,206 systemic exposure, measured as the plasma concentration of CP-675,206 4 weeks postdosing (C4 week), observed in patients with and without clinical benefit (CBR). The target C4 week indicated in the figure was established based on preclinical models of T-cell immunostimulation.
). The postinfusion plasma concentrations and area under the plasma disposition curve (AUC) both increase in an approximate proportional manner with dose. The clearance of CP-675,206 is low, 0.132 mL/h · kg; the volume of distribution is small, 81.2 mL/kg; and the terminal phase half-life is long, 22.1 days. These values are consistent with those of natural IgG2.25 There was no PK evidence of HAHA, nor were HAHA detected by immunoassay.
Logistic modeling of the data from patients with melanoma indicates that there is a statistically significant relationship between efficacy measured as clinical benefit response (CR, PR, or SD, and patient 14) and systemic exposure to CP-675,206 measured both as the AUC (P = .015) and the plasma concentration of CP-675,206 4 weeks postdosing (P = .006, Fig 3B). The predicted probability of experiencing a clinical benefit response without exposure to CP-675,206 is 0.077 (90% CI, 0.020 to 0.247). In contrast, the predicted probability of clinical benefit response at the highest value of AUC seen in this study is 0.843 (90% CI, 0.184 to 0.992). Based on preclinical models of T-cell immunostimulation, the target plasma concentration of CP-675,206 4 weeks postdosing was 30 μg/mL.12 Almost all of the patients who experienced clinical benefit response had a plasma concentration of CP-675,206 4 weeks postdosing greater than this target value (Fig 3C).
Discussion
This single-dose, dose-escalation, phase I trial demonstrates that CP-675,206 can be administered safely to patients. CP-675,206 administration resulted in breaking peripheral tolerance to self-tissues, with the development of autoimmune thyroiditis, colitis, and vitiligo in a subset of patients. Although it was not specifically designed to detect tumor responses, this study also provided evidence of antitumor activity in melanoma. The clinical tumor behavior after therapy, with evidence of delayed responses after apparent disease progression, may limit the immediate application of standard tumor measurement criteria for this agent. We also observed unusually favorable courses among several patients without objective response after dosing, which may be reflective of a less aggressive natural course of their disease or a more difficult to predict positive impact of CP-675,206 on their disease. Despite these caveats, it is remarkable that CP-675,206 induced long-lasting objective tumor responses in a subset of patients. The outcome of patients entered onto the 15 mg/kg cohort is particularly striking. Two of five patients with measurable disease had objective responses (one CR and one PR). One patient was conservatively labeled as having PD despite the regression of most lesions but increase in size in a single lesion (found to have a marked inflammatory response). Together with two other patients who had PD in this cohort, no relapses have been noted after local treatment during a mean follow-up time of 24+ months (Table 3). The sixth patient had regression of subcentimeter (considered nonmeasurable) nodular metastases in the lung, and relapsed with brain metastasis 18 months after the single CP-675,206 dose.
The protocol prospectively defined the MTD as the dose immediately below the cohort in which two of six patients developed grade 3 to 4 toxicities. On the basis of this criterion, dose-escalation was halted at 15 mg/kg, and 10 mg/kg was declared the MTD. However, we believe that higher dose levels warrant further exploration, since higher plasma levels correlated with antitumor responses and toxicities resolved without using immunosuppressant therapy. Furthermore, DLT in this trial were defined in the absence of specific supportive interventions, and more aggressive management of the observed toxicities may certainly allow further dose escalation. When the toxicity, response rate, and duration of antitumor response at the high-dose cohorts is compared with standard US Food and Drug Administration–approved therapies, it is evident that the therapeutic window of CP-675,206 can be further explored. All patients treated with high-dose IL-2 routinely experience grade 3 to 4 toxicities, with an overall median survival of 1 year and 5% to 10% of long-term survivors.26,27 The only other US Food and Drug Administration–approved therapy for melanoma, dacarbazine (DTIC), has an 6% to 12% response rate and a median survival less than 8 months in randomized, controlled trials.28,29 In randomized trials, combination chemotherapy does not improve survival compared to DTIC alone,30 and biochemotherapy is not superior to combination chemotherapy.29 Based on all these considerations, we believe that the current study does not fully define the optimal dose of CP-675,206 for phase II-III testing, and further exploration of dose and schedule is ongoing.
The ability of CTLA4 blockade to impact the natural history of patients with cancer is further suggested by three prior reports of human studies with the CTLA4 blocking antibody MDX-010.14-16 A single-dose study of 3 mg/kg therapy demonstrated biologic activity,14 and repeated dosing together with a peptide vaccine led to objective long-lasting responses in three of 14 patients.15 CTLA4 polymorphisms were suggested to be involved in autoimmune phenomena after administration in the adjuvant setting in patients with resected stage III or IV melanoma, and induced expression of the gut-homing chemokines CCR9 may correlate with the frequent gastrointestinal findings in this study.16
The combination of a vaccine and CTLA4 blockade is supported by preclinical studies in murine models, where a vaccine, or another form of immune activation like T-reg cell depletion, is required in addition to CTLA-4 blockade to induce regressions in nonimmunogenic tumors31,32 (most human cancers should be considered nonimmunogenic, since they grow progressively despite an intact immune system). Additionally, it is conceptually appealing that an immune intervention aimed at avoiding that the immune system is turned off may benefit from a prior turning on of the immune system against the cancer with a vaccine. Several of our patients received prior vaccines (Tables 1 and 3), but in the limited set of patients with objective responses, it is not clearly evident that prior vaccination is required to receive clinical benefit from CP-675,206. Two of the four patients with objective responses in the current study had not received prior vaccination, one had not received prior systemic therapy for metastatic disease, and one entered after progression to biochemotherapy with no prior vaccination. Therefore, contrary to prior clinical experiences with MDX010,14,15 the results of our study suggest that a single dose of CTLA4-blocking antibody can induce clinical responses in patients with melanoma without prior vaccination.
Most patients in this series received a single dose of CP-675,206, and response was assessed after this dose. Some patients were eligible for redosing at a higher dose level if they had been entered in the first three cohorts, which were deemed to achieve plasma levels of circulating CP-675,206 below the target of 30 μg/mL. The only patient with change in the response assessment after redosing was patient 120, who had SD for 7 months at redosing at 6 mg/kg, while had disease progression when initially dosed at 1 mg/kg. This patient had small volume and slow-growing lung metastasis throughout this period, and it is unclear whether CP-675,206 had any impact on the disease progression or the disease stabilization after redosing was a reflection of the natural course of his disease. Other patients received redosing with CP-675,206 after documenting clinical benefit after the initial dose. However, this study cannot provide evidence that redosing contributed to their response or duration of response. It is notable that patient 13 in this series had a CR after a single dose, and has not received any further therapy while being on continued CR for over 2 years.
In conclusion, CP-675,206 is an IgG2 human monoclonal antibody with encouraging antitumor activity in patients with advanced melanoma and an acceptable safety profile. Clinical efficacy increased with systemic exposure, and most cases of clinical benefit were noted above the predicted therapeutic plasma concentration of 30 μg/mL. Further evaluation of the antitumor activity of CP-675,206 is being pursued in malignant melanoma.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Authors
Employment
Leadership
Consultant
Stock
Honoraria
Research Funds
Testimony
Other
Antoni Ribas
Pfizer (A)
Pfizer (C)
Luis H. Camacho
Pfizer (C)
Gabriel Lopez-Berestein
Pfizer (A)
Dmitri Pavlov
Pfizer (N/R)
Cecile A. Bulanhagui
Pfizer (N/R)
Pfizer (B)
Robert Millham
Pfizer (N/R)
Pfizer (B)
James M Reuben
Pfizer (B)
Charla A. Parker
Pfizer (A)
Amarnath Sharma
Pfizer (N/R)
Jesus Gomez-Navarro
Pfizer (N/R)
Pfizer (B)
Pfizer (C)
Dollar amount codes: (A) < $10,000 (B) $10,000-99,999 (C) ≥ $100,000 (N/R) Not Required
Acknowledgments
We thank Deborah Porter; Ann Alcasid; Candida L. Lionetti; Judy Bresserer; Doug Hansen, PhD; Kelly Page; John Cuzmano; Karen Ferrante, MD; Huong T. Vu; Maribel Ontiveros; Rosalinda Rivera; Marily Elopre, RN; Clement Nzegwu; Brigitte Englahner, RN; Denise Oseguera, RN; Shawn Bachelor; and Victoria A. Dwyer for their dedication and excellent contribution to the conduction of this study. We also thank Victor Prieto, MD, and Hafeez Diwan, MD, from M.D. Anderson Cancer Center, for pathologic analysis of biopsies.
Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
References
1.
Shankaran V, Ikeda H, Bruce AT, et al: IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410::1107,2001-1111,
Chambers CA, Kuhns MS, Egen JG, et al: CTLA-4-mediated inhibition in regulation of T cell responses: Mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 19::565,2001-594,
Paust S, Lu L, McCarty N, et al: Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc Natl Acad Sci USA 101::10398,2004-10403,
Mellor AL, Chandler P, Baban B, et al: Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase. Int Immunol 16::1391,2004-1401,
Tivol EA, Borriello F, Schweitzer AN, et al: Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3::541,1995-547,
Hansen D, Canniff P, Primiano M, et al: Preclinical in vitro characterization of anti-CTLA4 therapeutic antibody CP-675,206. Proc Am Assoc Cancer Res, 2004 (abstr 3802)
Hodi FS, Mihm MC, Soiffer RJ, et al: Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 100::4712,2003-4717,
Phan GQ, Yang JC, Sherry RM, et al: Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 100::8372,2003-8377,
Sanderson K, Scotland R, Lee P, et al: Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol 23::741,2005-750,
Chatenoud L, Ferran C, Legendre C, et al: In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids. Transplantation 49::697,1990-702,
Wing MG, Moreau T, Greenwood J, et al: Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells. J Clin Invest 98::2819,1996-2826,
Byrd JC, Waselenko JK, Maneatis TJ, et al: Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol 17::791,1999-795,
Lee SY, Lee YH, Shin C, et al: Association of asthma severity and bronchial hyperresponsiveness with a polymorphism in the cytotoxic T-lymphocyte antigen-4 gene. Chest 122::171,2002-176,
Ribas A, Glaspy JA, Lee Y, et al: Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy. J Immunother 27::354,2004-367,
Phan GQ, Attia P, Steinberg SM, et al: Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 19::3477,2001-3482,
Chang E, Rosenberg SA: Patients with melanoma metastases at cutaneous and subcutaneous sites are highly susceptible to interleukin-2-based therapy. J Immunother 24::88,2001-90,
Middleton MR, Grob JJ, Aaronson N, et al: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18::158,-66
Eigentler TK, Caroli UM, Radny P, et al: Palliative therapy of disseminated malignant melanoma: A systematic review of 41 randomised clinical trials. Lancet Oncol 4::748,2003-759,
Falkson CI, Ibrahim J, Kirkwood JM, et al: Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: An Eastern Cooperative Oncology Group study. J Clin Oncol 16::1743,1998-1751,
McCoy KD, Hermans IF, Fraser JH, et al: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) can regulate dendritic cell-induced activation and cytotoxicity of CD8(+) T cells independently of CD4(+) T cell help. J Exp Med 189::1157,1999-1162,
Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al: Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194::823,2001-832,
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
From the Departments of Medicine, Division of Hematology/Oncology; Surgery, Division of Surgical Oncology and UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA; Departments of Experimental Therapeutics, Melanoma Medical Oncology and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Pfizer Global Research and Development, Groton-New London, CT
Address reprint requests to Luis H. Camacho, MD, MPH, Phase I Program/Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 422, Houston, TX 77030; e-mail: [email protected].
Antitumor Activity in Melanoma and Anti-Self Responses in a Phase I Trial With the Anti-Cytotoxic T Lymphocyte–Associated Antigen 4 Monoclonal Antibody CP-675,206. JCO23, 8968-8977(2005).
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
Antoni Ribas, Luis H. Camacho, Gabriel Lopez-Berestein, Dmitri Pavlov, Cecile A. Bulanhagui, Robert Millham, Begoña Comin-Anduix, James M. Reuben, Elisabeth Seja, Charla A. Parker, Amarnath Sharma, John A. Glaspy, Jesus Gomez-Navarro
