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Clinical Cancer Research Vol. 9, 3929S-3937S, September 1, 2003
© 2003 American Association for Cancer Research

Session III: EXPERIMENTAL RADIOIMMUNOTHERAPY

Low-Dose Radioimmunotherapy (90Y-PAM4) Combined with Gemcitabine for the Treatment of Experimental Pancreatic Cancer1

David V. Gold2, Keith Schutsky, David Modrak and Thomas M. Cardillo

Garden State Cancer Center, Belleville, New Jersey 07109


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Purpose: Monoclonal antibody PAM4 is reactive with the MUC1 mucin as expressed by >85% of human pancreatic cancers. Significant antitumor effects have been demonstrated using radiolabeled PAM4 for radioimmunotherapy (RAIT) of experimental pancreatic cancer. The goal of the present study was to determine whether the addition of low-dose 90Y-PAM4 RAIT to a clinically relevant regimen of gemcitabine chemotherapy would provide enhanced antitumor efficacy over that observed by chemotherapy alone without the addition of significant toxicity to normal tissues.

Experimental Design: Mice bearing human pancreatic tumor xenografts (CaPan1) were administered three cycles of gemcitabine chemotherapy (1000 mg/m2/week for 3 weeks with 1 week off) concomitant with 90Y-labeled PAM4 RAIT (25 µCi; 10% of the single agent MTD) given at weeks 0, 4, and 7. Control groups of mice received chemotherapy alone, 90Y-PAM4 RAIT alone, or an equidose of 90Y-labeled nontargeting control antibody with and without gemcitabine.

Results: Mice that received 90Y-PAM4 RAIT with gemcitabine had tumors that were significantly smaller in size than all of the other treatment groups (P < 0.005). A median survival of 24 weeks was achieved in mice that received the combined treatment versus 10 weeks for mice that received only gemcitabine (P < 0.001) and 16 weeks for mice that received only 90Y-PAM4 RAIT (P < 0.040). The combined treatment regimen was well tolerated.

Conclusions: A combined chemoimmunotherapy and RAIT approach using gemcitabine and low-dose 90Y-PAM4 provided significantly increased antitumor efficacy than was observed for each treatment arm given alone. Importantly, the enhanced antitumor efficacy was achieved with minimal toxicity to normal tissues. These studies provide justification for clinical trials using the combined modality treatment for patients with pancreatic cancer.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
In recent years, clinical trials have turned toward the combination of radiation and chemotherapy for the management of pancreatic cancer (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11) . The two modalities may have independent activity against tumor cell subpopulations, with cells that are intrinsically resistant to one modality being sensitive to the other. Chemotherapy may delay the regrowth of tumor cells that are sensitive to radiation, thus increasing tumoricidal effects. By causing cell cycle synchronization and cell cycle arrest, chemotherapy can increase the fraction of tumor cells in a radiosensitive phase of the cell cycle (12, 13, 14) . On the other hand, radiotherapy is also capable of inducing cell cycle synchronization, which might then increase the effectiveness of chemotherapy (15) .

Gemcitabine, cisplatin, and 5-fluorouracil are approved front-line chemotherapeutics for the treatment of pancreatic cancer. In addition to their toxic effects upon the tumor, they each have the ability to radiosensitize tissues. This makes them ideal chemotherapeutics to combine with radiation therapy, and as noted above, several clinical trials are being performed with a combined radiosensitizer/radiation therapy regimen. However, radiosensitizing drugs affect normal tissues as well as the tumor. Thus, dose-limiting toxicities, most frequently hematological and/or gastrointestinal, present formidable challenges (7 , 9 , 16) . In addition, application of conventional radiotherapy procedures (external, internal beam technologies, seed implants, and so forth) do not allow for the treatment of distant, perhaps unknown, metastatic sites. Indeed, although the treatment may bring the primary tumor site under control, virtually all patients succumb to distant metastases. In contrast, the use of a tumor-targeting antibody to deliver a high concentration of radioisotope to the tumor, be it primary or distant metastatic disease, with minimal radiation dose to normal tissues, may provide the means to increase tumoricidal activity at all tumor sites while maintaining acceptable levels of normal tissue toxicity.

mAb3 PAM4 is reactive with the MUC1 antigen as it is expressed by an overwhelming majority of pancreatic cancers (17) . Over the past few years, we have provided evidence as to its potential for clinical detection and therapy of pancreatic cancer. High concentrations of radiolabeled PAM4 were shown to target to xenografted human tumor models (18 , 19) and, more importantly, to the majority of pancreatic tumors within initial groups of patients (20 , 21) . Of special note, PAM4 showed no evidence of targeting in one patient who was later discovered to have had chronic pancreatitis rather than neoplastic disease. Administration of radiolabeled PAM4 to tumor-bearing animals provided cure for small tumors (<=0.25 cm3) and significantly extended survival (>5-fold) for animals bearing large tumors (>=1.0 cm3, ~5% of body weight; Refs. 22 , 23 ). Radiolabeled PAM4 antibody can target and provide irradiation of both primary and metastatic lesions while keeping nontumor toxicities within acceptable levels. Thus, this form of targeted radiation therapy, in combination with chemo/radiosensitization, may provide an increased window of opportunity for the effective treatment of pancreatic cancer that cannot be obtained by conventional radiation treatment procedures. Toward this end, the current work describes the application of multiple cycles of low-dose 90Y-PAM4 RAIT in combination with gemcitabine for the treatment of pancreatic cancer.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Experimental Animal Model.
The human pancreatic tumor, CaPan1, was obtained as a cell culture from the American Type Culture Collection (Manassas, VA). Solid tumors were initially started by injecting 107 cells into the right flank of 5-week-old, female athymic nu/nu mice (Taconic, Germantown, NY). Once tumors had grown to ~1 cm3, they were serially propagated by s.c. injection of 0.25 ml of a 20% (w/v) tumor suspension prepared by mincing the tumors in 0.9% saline with subsequent passage through a 40-mesh wire screen. CaPan1 cells produced moderate- to well-differentiated tumors. Tumors used in this study were passaged <10 times. Animal studies were approved by the Garden State Cancer Center’s Institutional Animal Care and Use Committee and performed in accordance with the American Association of Laboratory Animal Care, United States Department of Agriculture, and Department of Health and Human Services regulations.

111In- and 90Y-Radiolabeling of Antibody.
The purification and characterization of cPAM4 and isotype-matched, control hLL2 anti-CD22, B-cell lymphoma mAb have been described previously (17 , 24) . hLL2 was provided by Immunomedics, Inc. (Morris Plains, NJ). DOTA (Macrocyclics, Inc., Richardson, TX) was conjugated to cPAM4 IgG by a previously described method (25 , 26) . Briefly, the antibodies were made metal free and exchanged with the conjugation buffer using a series of dialyzes in 0.25 M ammonium acetate (pH 7.0), containing 20 mM DTPA; 0.25 M ammonium acetate (pH 7.0); and 0.1 M potassium phosphate-0.1 M sodium bicarbonate (pH 8.5) buffers. Conjugation was performed by adding a 90-fold excess of activated DOTA to the IgG mAbs and adjusting the pH to between 8.1 and 8.3. The antibody preparations were then incubated at 4°C for 18 h. The final product was purified by a series of dialyzes before they were sterile filtered through a 0.22-µm filter. The DOTA content was determined to be 6.7 residues/IgG molecule. An enzyme immunoassay (17) was used to demonstrate that immunoreactivity of the DOTA-labeled cPAM4 was not compromised by the labeling procedure. 90Yttrium-chloride (NEN Life Science Products, Inc., Boston, MA) or 111indium-chloride (Iso-Tex Diagnostic, Inc., Friendswood, TX) was added to a reaction vial with DOTA-cPAM4 IgG at a ratio of 5 mCi/mg cPAM4. The reaction was incubated at 45°C for 15 min and then quenched by removal from the heat source and addition of 0.1 volumes of 100 mM DTPA to chelate any 111In and/or 90Y that remains unbound to antibody. This mixture was then incubated at room temperature for 5 min. A volume of 1% human serum albumin in PBS was added to give a final activity concentration of ~1 mCi/ml for 111In- and ~5 mCi/ml for 90Y-DOTA-cPAM4. The specific activities for the 111In-cPAM4 and the 111In-hLL2 were 1.31 and 0.81 µCi/µg, respectively. Both labels had <5% unbound material and <5% aggregated material. The specific activity for the 90Y-DOTA-cPAM4 was in the range of 3.93–5.08 mCi/mg with <12% unbound 90Y, whereas the 90Y-DOTA-hLL2 was in the of range of 3.87–4.94 mCi/mg with <9% unbound 90Y. Molecular sieve HPLC demonstrated a single major peak of radioactivity coinciding with the elution volume of native, whole IgG. Thus, no additional purification of the radiolabeled mAbs was deemed necessary. The final labeled antibody product was placed in a dose calibrator (Capintec CRC15R, Ramsey, NJ) and the time and activity recorded. The immunoreactive fraction was determined by combining ~25 ng of radiolabeled antibody with an excess of MUC1 antigen, followed by incubation at 37°C for 1 h. This mixture was then applied to a column (0.5 x 60 cm) of Sepharose 4B (Amersham Pharmacia Biotech, Piscataway, NJ) eluted with PBS. Fractions of 0.5 ml were collected and counted in a Cobra II Auto-{gamma} counter (Packard Instrument, Meriden, CT). Earlier elution of radiolabeled antibody indicated immunoreactive material. Immunoreactivity of the 90Y-cPAM4 was in the range 82–92%.

Antibody/Gemcitabine Biodistribution Studies.
Initial tumor volume was determined by caliper measurements in three dimensions and calculated by length x width x depth. Mice-bearing tumors of similar size were placed into groups of 8–10 animals/time point. One group received an i.v. injection of 25 µCi 111In-labeled mAb alone on day 0, whereas a second group received the radiolabeled mAb on day 0 plus 6 mg of gemcitabine hydrochloride (Eli Lilly and Company, Indianapolis, IN) by i.p. injection. This dose was chosen to approximate the human dose of 1000 mg/m2/week. On the basis of the formula to calculate the surface area of a mouse (27) , m2 = 7.9 x (body weight)2/3/104, the equivalent dose given to a 20-g mouse is 6 mg. Radiolabeled mAb was augmented with unlabeled mAb to ensure that each mouse received a total of 50 µg of antibody. Groups of mice were sacrificed on days 1, 4, and 7 (approximately two half-lives for 90Y). The tumors, as well as various tissues (liver, spleen, kidney, lung, blood, pancreas, stomach, small intestine, large intestine, muscle, bone, and washed bone), were removed, weighed, and the radioactivity determined in a two-channel {gamma}-scintillation counter. Data were expressed as percentage of %ID/g. Student’s t test was used to assess significant differences.

Combined Gemcitabine and RAIT Treatment Protocol.
Mice bearing tumors of similar size were placed into groups of 9–10 mice (tumor size at start of study: 0.43 ± 0.18 cm3) that were treated with 25 µCi of 90Y-cPAM4 with and without gemcitabine or equidose control 90Y-hLL2 with and without gemcitabine. Two other control groups consisted of mice receiving gemcitabine alone and mice that were left untreated. Those mice that received gemcitabine were given three cycles of a standard regimen, 6 mg of gemcitabine hydrochloride by i.p. injection once/week for 3 weeks followed by 1 week of rest. Radiolabeled mAb was augmented with unlabeled mAb to ensure that each mouse received a total of 50 µg of antibody. Body weight (a measure of toxicity) was measured once a week for the entire study period. Measurements for determination of tumor size were likewise performed on a weekly basis. Mice were sacrificed at a point in time when tumor size was >=5.0 cm3 (~2.5 g).

In a separate study, groups of nontumor-bearing mice (n = 10 mice/group) were administered either the combined 90Y-cPAM4 RAIT with gemcitabine treatment regimen, gemcitabine alone, or were left untreated. Five mice from each group were bled from the retro-orbital sinus on alternating weeks to lessen the impact that would occur by repeated bleeding of the same mice. After lysing the RBCs and washing the WBCs in PBS, the cells were resuspended in 1 ml of 1% formalin in FACS Flow Sheath (Becton Dickinson Immunocytometry Systems, San Jose, CA). Samples were analyzed in a FACSCalibur (Becton Dickinson Immunocytometry Systems) and WBC numbers determined using the Cell Quest software package (Becton Dickinson Immunocytometry Systems).

Data Analysis.
Statistical analyses for the tumor growth data were based on AUC and survival time. Profiles of individual tumor growth were obtained through linear and exponential curve modeling. The Q test was used to examine data sets for inclusion/exclusion of individual data points. One animal (from a total of 10) within the test group given 90Y-cPAM4 with gemcitabine was excluded with a confidence level of 99%. Tumor growth within this animal was similar to that observed for the untreated group. Student’s t test was used to assess statistical significance between any two groups. As a consequence of incompleteness on some of the growth curves (because of deaths), statistical comparisons of AUC were performed only up to the time at which the first animal within a group was sacrificed. AUC analyses were supported by statistical comparisons of survival data; in this case, survival was defined as time for a tumor to reach 5.0 cm3. At the termination of the study, some of the animals had not yet experienced the end point and their observations were considered as censored. The Mantel-Haenszel log-rank test was then used for comparison of treatment arms (28) .


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
To determine the potential impact gemcitabine might have on the biodistribution of radiolabeled cPAM4, mice bearing s.c. xenografts of the CaPan1 human pancreatic adenocarcinoma were given 111In-DOTA-cPAM4 with or without concomitant gemcitabine. Overall, the addition of gemcitabine did not alter the normal biodistribution of cPAM4. Tumor uptake of 111In-DOTA-cPAM4 was not significantly different between the two groups of mice (Table 1)Citation . The only statistically significant differences were in the liver on day 7 (P < 0.040) and the kidneys, pancreas, and blood on day 4 (P < 0.038). However, in absolute terms these differences were minor (<1.5%ID/g). A control mAb, hLL2, likewise labeled with 111In and injected into tumor-bearing mice with or without gemcitabine, showed several statistically significant differences in tissue uptake. In absolute terms, the only major differences were in the bone and bone marrow where the %ID/g values were 1.6–2.7 times greater in the presence of gemcitabine (P < 0.007). The increased bone uptake was not strictly attributable to activity in the bone marrow because washed bone (bone marrow was flushed out with saline) also had uptake that was significantly higher in the presence of gemcitabine (2.26 ± 0.25, 2.53 ± 0.53, and 2.09 ± 0.72 versus 4.83 ± 1.40, 4.29 ± 1.00, and 3.66 ± 0.79%ID/g for days 1, 4, and 7 in the absence and presence of gemcitabine, respectively). It should be noted that the two groups, 111In-DOTA-hLL2 with and without gemcitabine, received the same reagent batch of radiolabeled antibody.


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  		Table 1 Biodistribution data for 111In-labeled cPAM4 and control hLL2 with or without concurrent gemcitabine administration

 
Tumor-bearing mice injected with 111In-DOTA-cPAM4 and gemcitabine had significantly higher tumor uptake than those mice that received 111In-DOTA-hLL2 and gemcitabine at all time-points (1.7-, 2.3-, and 1.8-fold higher on days 1, 4, and 7, respectively, P < 0.021). Conversely, 111In uptake in normal tissues was significantly higher in the mice that received both the hLL2 and gemcitabine in comparison to the mice that received cPAM4 and gemcitabine (P < 0.038). A comparison of the t1/2 values for blood indicated that 111In was cleared twice as fast from the blood of mice that received the cPAM4 with gemcitabine (t1/2 = 28 h) than from those that received hLL2 and gemcitabine (t1/2 = 56 h).

Mice bearing s.c. CaPan1 human pancreatic cancer xenografts (~0.5 cm3 at the start of the study) received three cycles of a standard gemcitabine chemotherapy regimen [6 mg for a 5-week old (20 g) athymic nu/nu mouse for 3 weeks with 1 week off] with or without a low dose (25 µCi) of 90Y-cPAM4 RAIT administered at weeks 0, 4, and 7. Control groups received either low-dose (25 µCi) 90Y-cPAM4 alone, three doses at weeks 0, 4, and 7; three cycles of equidose-nontargeting control 90Y- hLL2 RAIT with or without gemcitabine as above; and a final group that remained untreated. The mean tumor volumes from the various treatment groups, normalized to day 0, are presented in Fig. 1Citation with survival curves provided in Fig. 2Citation . Survival was defined as the time it took for a tumor to reach 5.0 cm3. Values for AUC of individual animals, response rates, and survival analyses were used to compare the antitumor effects of the different treatment procedures. Statistical comparisons for tumor growth were performed at the last assessable time point; that is at a point in time at which mice from one of the groups was sacrificed because of tumor burden (>5 cm3).



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  		Fig. 1. Low-dose 90Y-PAM4 (25 µCi), coadministered with standard gemcitabine chemotherapy (3 cycles). Mice bearing s.c. CaPan1 tumors (~0.5 cm3) received one of six possible treatments as described in the "Materials and Methods." Tumors were measured weekly until they reached >5.0 cm3, at which time the mouse was sacrificed. Mean tumor sizes normalized to day 0. Data ends for each group once mice within a given group begin to succumb to disease activity.

 


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  		Fig. 2. Survival curves for mice treated with standard gemcitabine chemotherapy combined with low-dose RAIT.

 
When compared with the untreated group, neither gemcitabine alone, 90Y-hLL2 alone, nor 90Y-hLL2 with gemcitabine provided an observable, antitumor effect. Mice within each of these groups had rapidly progressing tumors. Median survival times (Table 2)Citation , as well as analyses of AUC, revealed no statistically significant differences between these groups (all Ps for AUC and survival analyses were >0.07).


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  		Table 2 Multiple cycle low-dose 90Y-PAM4 RAIT with gemcitabine chemotherapy

Survival Analysis at week 26.

 
The MTD for administration of a single dose of single-agent 90Y-cPAM4 was previously shown to be 260 µCi (23) and when administered as a single dose with gemcitabine, 100 µCi. In the current study, injection of multiple cycles of low-dose 90Y-cPAM4 (25 µCi; ~10% of the single-agent MTD) provided significant inhibition of tumor growth as compared with the untreated group. Already at week 4, the last assessable time point for the untreated mice, the group of mice given 90Y-cPAM4 without gemcitabine had tumors that were approximately one-half the size of tumors from the untreated group [1.11 ± 0.56 versus 2.59 ± 1.73 cm3, respectively (AUC, P < 0.044)]. However, no significant differences were noted when comparing the group treated with 90Y-cPAM4 as a single agent to the groups that received gemcitabine alone or 90Y-hLL2 with gemcitabine.

When low-dose 90Y-cPAM4 RAIT was added to a standard regimen of gemcitabine therapy, we observed significantly greater inhibition of tumor growth than was provided by any of the other treatment procedures. At week 4 (the end of the first treatment cycle), this group of mice had tumors that were approximately one-fifth the size of tumors from the untreated mice [0.53 ± 0.34 versus 2.59 ± 1.73 cm3, respectively (AUC, P < 0.010)]. Furthermore, the tumors in mice treated with combined 90Y-cPAM4 RAIT with gemcitabine were significantly smaller in size than either treatment arm alone; approximately 30% of the size of tumors in mice that received only gemcitabine at week 5 [0.55 ± 0.41 versus 2.41 ± 1.62 cm3, respectively (AUC, P < 0.002)] and ~40% of the size of tumors in mice that received 90Y-cPAM4 RAIT alone at week 7 [0.43 ± 0.40 versus 2.07 ± 1.95 cm3, respectively (AUC, P < 0.005)]. Comparisons to the 90Y-hLL2 RAIT groups, with or without gemcitabine, demonstrated the specificity of the antibody-targeted antitumor effect. These treatment groups were each significantly less tumoricidal than the cPAM4 RAIT with gemcitabine treatment group (AUC, P < 0.001 for comparison with 90Y-hLL2 alone at week 6 and P < 0.001 for comparison with 90Y hLL2 with gemcitabine at week 7).

These results translated into a significantly extended survival time (Fig. 2Citation and Table 2Citation ) for the group of mice that received combined low-dose 90Y-cPAM4 RAIT with gemcitabine. Median survival time for this group of mice was 24 versus only 8.5 weeks for untreated mice (P < 0.001), 10 weeks for gemcitabine-treated mice (P < 0.001), and 16 weeks for the group administered 90Y-cPAM4 alone (P < 0.040).

At the end of the three cycles of treatment, i.e., week 10, the group that received 90Y-cPAM4 alone (n = 9) had 1 PR (tumor size decreased to <=50% of the original tumor size), whereas the 90Y-cPAM4 with gemcitabine group (n = 9) had 1 CR with 3 PRs and 2 mice with stable disease (tumor size between 50 and 125% of original tumor size). In contrast, all of the animals within the other groups showed progressive disease from the onset. More significantly, at the end of the 26-week study period, there were 4 CRs among those mice treated with the combined low-dose 90Y-cPAM4 with gemcitabine.

The administration of 90Y-cPAM4 RAIT concomitant with gemcitabine was well tolerated. There were no treatment-related deaths in any of the groups. In addition, the average loss in body weight was <2% over the 10-week treatment period for each of the treatment groups (Fig. 3)Citation . As an additional measure of potential toxicity, peripheral WBC counts were obtained (Fig. 4)Citation . The only significant differences between WBC counts from untreated mice and mice treated with the combination therapy were at weeks 6 and 7 (weeks 2 and 3 of the second cycle). A ~40% drop in the WBC counts was observed at these time points (15,888 ± 8,020 and 14,627 ± 2,312 versus 9,227 ± 1,582 and 8,250 ± 3,413 WBC/mm3 for untreated and combined modality treated mice at weeks 6 and 7, P < 0.030 and <0.002, respectively). At week 3, there was a significant drop in WBC counts in the mice treated with gemcitabine alone (1927 ± 621 WBC/mm3) when compared with the untreated group (9078 ± 3992 WBC/mm3, P < 0.0003). However, by the next week (start of second cycle), the WBC counts recovered (8766 ± 1593 WBC/mm3) and were not significantly different from the untreated or combined treatment group.



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  		Fig. 3. Body weight as a measure of toxicity. Body weight was measured weekly. Loss of >20% from initial weight was considered toxic and the animal sacrificed. Mean body weight is shown as a percentage of starting body weight.

 


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  		Fig. 4. WBC counts as a measure of toxicity. WBC counts were determined weekly. The means ± SDs are shown.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Despite the best efforts of current treatment procedures, pancreatic cancer remains one of the most deadly forms of cancer. Many of the therapeutic strategies used use a combination of modalities. These include surgical resection when possible, radiotherapy, and/or chemotherapy. Chemotherapy, particularly the frontline drugs of choice for pancreatic cancer, gemcitabine, and 5-fluoruracil, render tumor cells more sensitive to the effects of ionizing radiation (reviewed in Ref. 13 ). Indeed, recent clinical trials have examined the efficacy of treating patients with chemotherapy and concomitant radiotherapy preoperatively in patients with resectable tumors (6 , 10 , 11) , as well as in patients with unresectable tumors (1 , 3 , 5 , 7, 8, 9) . In those few patients deemed to have resectable disease, a treatment regimen of chemotherapy and radiotherapy before surgery resulted in a higher number of individuals with negative margins around the tumor at the time of resection (6 , 10) with significantly fewer positive lymph nodes (10) . Overall, an increase in median survival was noted in these patients in comparison to those who received no treatment before surgery. Unfortunately, the increase in median survival was not always significantly longer. Although local and regional tumor recurrence is low, most patients eventually succumb to distant metastatic disease. For patients with nonresectable, advanced disease, the main objective for combined chemotherapy and radiotherapy treatment protocols is to provide palliation of disease symptoms (7, 8, 9) . Unfortunately, most of these patients also succumb to disease progression at metastatic sites. Thus, although treatment of the primary tumor site may be successful, the limitations in providing directed beam radiation to all tumor sites, metastatic as well as primary, is difficult at best. One potential means for overcoming this problem is the use of radiolabeled antibodies that are able to target metastatic as well as primary tumor sites with minimal reactivity to normal tissues.

The concept of combining chemotherapy with antibody-targeted radiation is attractive. The two modalities may have independent activity against tumor cell subpopulations, with cells that are intrinsically resistant to one modality being sensitive to the other. By causing cell cycle synchronization and cell cycle arrest, chemotherapy can increase the fraction of tumor cells in a radiosensitive phase of the cell cycle. On the other hand, RAIT alone is also capable of inducing cell cycle synchronization, which might then increase the effectiveness of chemotherapy. A considerable body of preclinical research now exists to support the application of RAIT in combination with chemotherapy for the treatment of cancer. These studies cover many tumor types [e.g., breast (29, 30, 31) , colorectal (32, 33, 34, 35) , and medullary thyroid (36, 37, 38) cancers and lymphomas (39 , 40) among others (41) ], as well as many chemotherapeutic agents [e.g., 5-fluorouracil (32, 33, 34) , doxorubicin (36, 37, 38) , Taxol (29 , 30 , 39 , 41) , topotecan (31) , and others (35 , 40 , 42) ]. Overall, the results for the combined modality approach indicate an enhanced antitumor effect when compared with either arm alone. Importantly, this is achieved with less toxicity than is provided by either treatment arm alone when used at its respective MTD.

As already noted, we have developed mAb PAM4 that shows high specificity for pancreatic cancer. In initial clinical trials using murine PAM4 high concentrations of the antibody were shown to target tumor in 8 of 10 patients, with 1 of the negative patients having chronic pancreatitis rather than pancreatic cancer (20 , 21) . In preclinical studies using large (1 cm3) CaPan1 xenograft tumors, we observed a ~60% cure rate at week 26 (the end of the study) in a group of mice administered a single MTD of 90Y-PAM4 (23) . Although we have had success with PAM4 as a therapeutic agent in murine model systems, we realize the lower concentration of radiolabeled antibody that will most likely be achieved within patient tumors may represent a substantial hurdle in the development of a clinically effective PAM4-based therapeutic agent. It is for this reason that we undertook the present studies to combine 90Y-labeled PAM4 RAIT with standard gemcitabine therapy.

We have examined two approaches toward this type of study, dependent upon which treatment arm was considered as the primary agent. In a previous set of studies, radiolabeled cPAM4 was considered the primary agent. We determined that a MTD of 100-µCi 90Y-cPAM4 could be given to mice in combination with gemcitabine provided as a radiosensitizing agent (2 mg given every 3 days for a total of five injections).4 This combination provided a 58% response rate; however, no CRs were observed at the end of the 26-week study period. For the present studies, we used gemcitabine as the primary agent with administration of a standard chemotherapy regimen (6 mg once/week for 3 weeks followed by 1 week off, then repeat for a total of three cycles). Nonreversible toxicity was not observed at this dose of gemcitabine, however, considering the precipitous drop in WBC, we may have come close to the MTD. Reports in the literature regarding this matter, unfortunately, have used varying schedules for administration of the drug. For example, one study has reported an MTD of 100 mg/kg when gemcitabine was administered every third day for a total of six injections (43) . For a 20-g mouse, this translates to 2 mg/injection or 6 mg/week, similar to what was used in our studies.

By addition of low-dose 90Y-cPAM4 RAIT (~10% of the single-agent MTD) to a standard gemcitabine therapy regimen, we observed significantly enhanced antitumor effects, with a median survival time 2.4-fold longer for the combined treatment group as compared with the group that received gemcitabine alone. Furthermore, we observed 4 of 9 CRs within the combined treatment group. This antitumor effect was because of the specific targeting of 90Y-cPAM4 to the tumor and not simply an effect attributable to whole-body irradiation by the high-energy 90Y isotope (Emax ß = 2.27 MeV) because equidose 90Y-hLL2 control antibody did not yield similar effects.

This initial preclinical study used 90Y as the therapeutic radionuclide of choice based on several factors, including energy emissions, maximum particle range, residualization properties, and half-life. Two other radionuclides with therapeutic possibilities are 177Lu and 188Re. 177Lu is a residualizing radiometal that emits less energy than 90Y (Emax ß = 496 KeV) but has a longer half-life (161 versus 64 h). Antitumor efficacy of 90Y or 177Lu radioisotopes conjugated to mAb-RS7 (reactive with epithelial glycoprotein-1) was compared in mice bearing s.c. human lung adenocarcinoma xenografts (Calu-3). No significant differences were observed between the two labels in terms of antitumor growth effects and overall survival (44) . However, 177Lu has a much shorter particle range than 90Y (1.5 versus 18 mm) that may make it less effective against larger tumors such as those encountered with pancreatic cancer. 188Re, on the other hand, is very similar to 90Y both in energy (Emax ß = 2.11 MeV) and maximum particle range (11 mm) but has a much shorter half-life (17 h). Because PAM4 IgG reaches maximum tumor uptake between 48 and 72 h after administration (23) , the shorter half-life of 188Re may not provide an adequate dose to tumor. In a preclinical study comparing 188Re-, 90Y-, and 131I-labeled mAb-Mu9 IgG (reactive with colon-specific antigen-p) in tumor-bearing mice (45) , the 188Re-labeled mAb was the least effective agent in controlling tumor growth. A major problem associated with 188Re was that chelation of 188Re was not as stable as the chelation provided by DOTA for 90Y. This added to the toxicity of the kidneys as the free 188Re was cleared. The authors in that study suggested that 188Re may be more useful when labeled to agents that target to tumors much more rapidly than whole IgG such as antibody fragments or tumor-specific peptides (45) .

When combining radiosensitizing drugs such as gemcitabine with radiotherapy, an important consideration is the potential for nontumor toxicity. Although generally tolerated, several clinical trials combining chemotherapy with external or internal beam therapy have reported dose-limiting toxicities (2 , 5 , 13 , 46) that did not permit sufficient escalation in either arm to achieve substantial antitumor effect. However, this type of combined modality approach may have value as a preoperative, neoadjuvant with follow-up restaging to determine feasibility of resection. Within the current preclinical RAIT-gemcitabine studies, it is important to note that a significant and substantial antitumor effect was observed without evidence of life-threatening toxicity. This is in contrast to previous studies where the MTD for 90Y-PAM4 was used (23) .

In conclusion, we have demonstrated that addition of low-dose 90Y-PAM4 to a standard clinical regimen of gemcitabine resulted in a significantly greater antitumor effect with prolonged survival when compared with gemcitabine alone, and that this was achieved with little additional toxicity. It should be noted that we have not attempted to optimize the protocol as to dose or timing of each treatment arm, nor have we investigated the effect of continued treatment as opposed to the limited three cycles of treatment given here. In addition, it may be that providing low-dose radiolabeled PAM4 more frequently (e.g., weekly or every third day) with standard gemcitabine dosing would enhance antitumor efficacy similar to the increased antitumor effects observed with fractionated dose RAIT procedures (47, 48, 49) . By combining PAM4 RAIT with current chemo- and/or traditional radiotherapies, we hope to provide a more effective treatment for pancreatic cancer whether it is used as a primary treatment for small volume disease (45 , 50) , an aggressive neoadjuvant procedure before attempting surgical resection, or subsequent to initial debulking of tumor by surgical and/or traditional radiation treatment procedures.


   FOOTNOTES
 
1 Presented at the "Ninth Conference on Cancer Therapy with Antibodies and Immunoconjugates," October 24–26, 2002, Princeton, NJ. This work was supported, in part, by New Jersey Commission on Cancer Research Grant 03-1105-CMM-N0 and United States Public Health Service Grant CA-54425. Back

2 To whom requests for reprints should be addressed, at Garden State Cancer Center, 520 Belleville Avenue, Belleville, NJ 07109. Phone: (973) 844-7025; Fax: (973) 844-7020; E-mail: dvgold{at}gscancer.org Back

3 The abbreviations used are: mAb, monoclonal antibody; hLL2, humanized LL2; cPAM4, chimeric PAM4; AUC, area under the curve; CR, complete reasponse; DOTA, tetraazacyclododecyltetraacetic acid; DTPA, diethylenetriaminepentacetic acid; MTD, maximum-tolerated dose; RAIT, radioimmunotherapy; %ID/g, injected dose/gram; CR, complete response; PR, partial response; 177Lu, lutetium-177; 188Re, rhenium-188. Back

4 D. V. Gold, D. E. Modrak, K. Schutsky, and T. M. Cardillo. Combined 90Yttrium-DOTA-Labeled PAM4 Antibody Radioimmunotherapy and Gemcitabine Radiosensitization for the Treatment of a Human Pancreatic Cancer Xenograft, manuscript in preparation. Back


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Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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