untitled h1
appendix 3

| Expected IL-2 Toxicities and their Management   |                                                                                                                                              |                                                                                                                                                 |                                                                  |      |
|-------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------|------|
| Expected toxicity                               | Expected                                                                                                                                     | Supportive Measures                                                                                                                             | Stop Cycle*                                                      | Stop |
| grade                                           | Treatment **                                                                                                                                 |                                                                                                                                                 |                                                                  |      |
| Chills                                          | 3                                                                                                                                            | IV Meperidine 25-50                                                                                                                             | No                                                               | No   |
| mg, IV q1h, prn,                                |                                                                                                                                              |                                                                                                                                                 |                                                                  |      |
| Fever                                           | 3                                                                                                                                            | Acetaminophen 650  mg, po, q4h;  Indomethicin 50-75  mg, po, q8h                                                                                | No                                                               | No   |
| Pruritis                                        | 3                                                                                                                                            | Hydroxyzine HCL  10-20 mg po q6h,  prn;  Diphenhydramine  HCL25-50 mg, po,  q4h, prn                                                            | No                                                               | No   |
| Nausea/ Vomiting/                               | 3                                                                                                                                            | Ondansetron 10 mg,                                                                                                                              |                                                                  |      |
| Anorexia                                        | IV, q8h, prn;  Granisetron 0.01  mg/kg IV daily prn;  Droperidol 1 mg, IV  q4-6h, prn;  Prochlorperazine 25  mg pr, prn or 10 mg  IV q6h prn | No                                                                                                                                              | No                                                               |      |
| Diarrhea                                        | 3                                                                                                                                            | Loperamide 2mg, po,  q3h, prn;  Diphenoxylate HCl  2.5 mg and atropine  sulfate 25 mcg, po,  q3h, prn; codeine  sulfate 30-60 mg, po,  q4h, prn | If uncontrolled after 24  hours despite all  supportive measures | No   |
| Malaise                                         | 3 or 4                                                                                                                                       | Bedrest                                                                                                                                         | If other toxicities occur                                        | No   |
| simultaneously                                  |                                                                                                                                              |                                                                                                                                                 |                                                                  |      |
| Hyperbilirubinemia                              | 3 or 4                                                                                                                                       | Observation                                                                                                                                     | If other toxicities occur                                        | No   |
| simultaneously                                  |                                                                                                                                              |                                                                                                                                                 |                                                                  |      |
| Anemia                                          | 3 or 4                                                                                                                                       | Transfusion with                                                                                                                                | If uncontrolled despite                                          | No   |
| PRBCs                                           | all supportive measures                                                                                                                      |                                                                                                                                                 |                                                                  |      |
| Thrombocytopenia                                | 3 or 4                                                                                                                                       | Transfusion with                                                                                                                                | If uncontrolled despite                                          | No   |
| platelets                                       | all supportive measures                                                                                                                      |                                                                                                                                                 |                                                                  |      |
| Edema/Weight gain                               | 3                                                                                                                                            | Diuretics prn                                                                                                                                   | No                                                               | No   |
| Hypotension                                     | 3                                                                                                                                            | Fluid resuscitation                                                                                                                             | If uncontrolled despite                                          | No   |
| Vasopressor support                             | all supportive measures                                                                                                                      |                                                                                                                                                 |                                                                  |      |  
| Dyspnea                 | 3 or 4                                                     | Oxygen or                                                                                                 | If requires ventilatory   | No            |
|-------------------------|------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------|---------------------------|---------------|
| ventilatory support     | support                                                    |                                                                                                           |                           |               |
| Oliguria                | 3 or 4                                                     | Fluid boluses or  dopamine at renal  doses                                                                | If uncontrolled despite   | No            |
| all supportive measures |                                                            |                                                                                                           |                           |               |
| Increased creatinine    | 3 or 4                                                     | Observation                                                                                               | Yes (grade 4)             | No            |
| Renal failure           | 3 or 4                                                     | Dialysis                                                                                                  | Yes                       | Yes           |
| Pleural effusion        | 3                                                          | Thoracentesis                                                                                             | If uncontrolled despite   | No            |
| all supportive measures |                                                            |                                                                                                           |                           |               |
| Bowel perforation       | 3                                                          | Surgical intervention                                                                                     | Yes                       | Yes           |
| Confusion               | 3                                                          | Observation                                                                                               | Yes                       | No            |
| Somnolence              | 3 or 4                                                     | Intubation for airway                                                                                     | Yes                       | Yes           |
| protection              |                                                            |                                                                                                           |                           |               |
| Arrhythmia              | 3                                                          | Correction of fluid  and electrolyte  imbalances; chemical  conversion or  electrical conversion  therapy | If uncontrolled despite   | No            |
| all supportive measures |                                                            |                                                                                                           |                           |               |
| Elevated Troponin       | 3 or 4                                                     | Observation                                                                                               | Yes                       | If changes in |
| levels                  | LV function  have not  improved to  baseline by  next dose |                                                                                                           |                           |               |
| Myocardial              | 4                                                          | Supportive care                                                                                           | Yes                       | Yes           |
| Infarction Elevated     | 3 or 4                                                     | Observation                                                                                               | For grade 4 without       | If changes    |
| transaminases           | liver metastases                                           | have not  improved to  baseline by  next dose                                                             |                           |               |
| Hyperbilirubinemia      | 3 or 4                                                     | Observation                                                                                               | For grade 4 without       | If changes    |
| liver metastases        | have not  improved to  baseline by  next dose              |                                                                                                           |                           |               |
| Electrolyte             | 3 or 4                                                     | Electrolyte                                                                                               | If uncontrolled despite   | No            |
| imbalances              | replacement                                                | all supportive measures                                                                                   |                           |               |
| Neutropenia             | 4                                                          | Observation                                                                                               | No                        | No            |  
*Unless the toxicity is not reversed within 12 hours ** Unless the toxicity is not reversed to grade 2 or less by next treatment.
untitled h1
appendix 4

| Table 8. Toxicity of Treatment with Interleukin-2   |       |           |       |      |      |     |     |       |
|-----------------------------------------------------|-------|-----------|-------|------|------|-----|-----|-------|
| Interleukin-2 Plus                                  | Alone | TNF       | a IFN | MoAB | CYT  | LAK | til | Total |
| Number of Patients                                  | 155   | 38        | 1210  | 32
35      | 19
30      | 214
348     | 66  | 652*  |
| Number of Courses                                   | 236   | 85        | 95    | 1039 |      |     |     |       |
| Chills                                              | 75    | 16        | 68    | 8    | 8    | 191 | 33  | 39    |
| Pruntus                                             | 53    | 9         | 26    | 2    | 2    | 82  | 6   | 180   |
| Necrosis                                            | 3     | l         | 2     | l    | l    | r   | l   | s     |
| Anaphylaxis                                         | l     | I         |       |      |      |     |     |       |
| l                                                   | l     |           |       |      |      |     |     |       |
| Mucositis (requiring liquid diet)                   | 6
1       | I         | 7     | 2    | 12   | 2   | 30  |       |
| l                                                   |       |           |       |      |      |     |     |       |
| Alimentation not possible                           | l     | l         | 12    | l    | 4    |     |     |       |
| Nausca and vomiting                                 | 162   | 42        | 17    | 14   | 20   | 263 | 48  | 666   |
| Diarrhea                                            | 144   | 38        | 98    | 15   | 13   | 250 | 38  | 5596  |
| Hyperbilirubinemia (maximum/mg %)                   | 126   | 97        | 21    | 190
22      | 46
26      |     |     |       |
| 6.1-10.0                                            | 49    | 18        | 547   |      |      |     |     |       |
| 12                                                  |       |           |       |      |      |     |     |       |
| .49                                                 | 3     | 00        | 9     | 179  |      |     |     |       |
| 26                                                  | 40    |           |       |      |      |     |     |       |
| 10.1+                                               | I     | 4         | l,    | 8    | 83   |     |     |       |
| Oliguria                                            |       |           |       |      |      |     |     |       |
| <80 ml/8 hours                                      | 81    | 37        | 67    | 14   | 9    | 114 | 25  | 347   |
| <240 ml/24 hours                                    | 19    | 2         | 3     | l    | 12   | s   | 42  |       |
| Weight gain (% body weight)                         |       |           |       |      |      |     |     |       |
| 000000                                              | 106   | 23        | 65    | 8    | 19   | 17  | 49  | 37    |
| 5.1-10.0                                            | 78    | 41        | 11    | 2    | 10   | 148 | 26  | 436   |
| 10.1-15.0                                           | 43    | 17        | 26    |      | 9    | 62  | 15  | 175   |
| 15.1-20.0                                           | 7     | 3         | 8     | i    | i    | 15  | 3   | 38    |
| 20.1+                                               | 2     | I         | l     | i    | 6    | 2   | 13  |       |
| Elevated creatinine (maximum/mg %)                  |       |           |       |      |      |     |     |       |
| 2.1-6.0                                             | 148   | 43        | 121   | 20   | 14   | 237 | 54  | 637   |
| 6.1-10.0                                            | 12    |           |       |      |      |     |     |       |
| 21
5                                                     | 1     | 14        | 3
1       | l    | 34   | 85  |     |       |
| 10.1+                                               | l     | I         | l     | 2    | 1    | 10  |     |       |
| Hematuria (gross)                                   | l     | -         | l     | 2    | l    | 2   |     |       |
| Edema (symptomatic nerve or vessel                  |       |           |       |      |      |     |     |       |
| compression)                                        | 4     | l         | 6     | l    | 7    | l   | 17  |       |
| Tissue ischemia                                     | l     | l         | i     | I    | l    | 2   |     |       |
| Resp. distress:                                     |       |           |       |      |      |     |     |       |
| not intubated.                                      | 17    | -         | 9     | 4    | I    | 28  | 7   | 67    |
| intubated                                           | 15    | l         | 6     | 3    | 12   | s   | 41  |       |
| l                                                   |       |           |       |      |      |     |     |       |
| Bronchospasm                                        | 2     | l         | 2     | l    | 4    | 9   |     |       |
| Pleural effusion (requiring                         |       |           |       |      |      |     |     |       |
| thoracentesis)                                      | 4     | l         | l     | 2    | s    | i   | 17  |       |
|                                                     |       |           |       |      |      |     |     |       |
| Somnolence                                          | 29    | COLOGICAL | 22    | 6    | <<   | 45  | 8
5     | 14    |
| Coma                                                | g     | 8         | 33    |      |      |     |     |       |
| 88                                                  | l     |           |       |      |      |     |     |       |
| Disorientation                                      | 52    | 50        | 7     | 89   | 10   | 215 |     |       |
| 17                                                  |       |           |       |      |      |     |     |       |
| Hypotension (requiring pressors)                    | 19    | 16        | 40    | 12.  | 259  | 45  | 508 |       |
| Angina                                              | 4     | l         | 08    |      | 8    | l   | 22  |       |
| Myocardial infarction                               | l     | l         | l     | l    | l    | 6   |     |       |
| 15                                                  | 13    | 3         | 39    | 78   |      |     |     |       |
| Arrythmias                                          | 2     | l         | 6     |      |      |     |     |       |
| Anemia requiring transfusion (number)               |       |           |       |      |      |     |     |       |
| units transfused)                                   |       |           |       |      |      |     |     |       |
| 1-15                                                | 77    | 16        | s3    | 9    | 2 6  | 176 | 40  | 377   |
| 6-10                                                | 22    | i         | 5
1       | 3    | 53   | 9   | 95  |       |
| 1-15                                                | 4
|       | l         | l     | l    | 15   | 4   | 24  |       |
| 16+                                                 | l     | I         | l     | l    | 11   | i   | 14  |       |
| Thrombocytopenia (minimum/mm3)                      |       |           |       |      |      |     |     |       |
| <20,000                                             | 28    | I         | 2     | 4    | 6    | 71  | 19  | 131   |
| 20,001-60,000                                       | 82    | 1         | 62    | 14   | 12   | 150 | 30  | 361   |
| 60,001-100,000                                      | 53    | 36        | 76    | 11   | 8    | 79  | 22  | 285   |
| Central line sepsis                                 | 113   | 7         | 4     | 36   | 15.2 |     |     |       |
| l                                                   | I     | 63        |       |      |      |     |     |       |
| i                                                   |       |           |       |      |      |     |     |       |
| Death                                               | 4     | l         | 3     | 10   |      |     |     |       |
| * Eleven patients are in two protocols.             |       |           |       |      |      |     |     |       |
certificate of analysis
appendix 4

Infused T cells transduced with MAGE-A3 DP0401/0402 TCR genes.  
Date of preparation of final product: Patient:
Tests performed on final product:  
| Test                      | Method                    | Limits              | Result   | Tests  Performed  by   | Initials/ Date   |
|---------------------------|---------------------------|---------------------|----------|------------------------|------------------|
| Cell viability1           | trypan blue exclusion     | >70%                |          |                        |                  |
| Total viable cell         | visual microscopic count  | >1 x107             |          |                        |                  |
| number1 Tumor reactivity2 | γ-IFN release vs. peptide | >200 pg/mL, and > 2 |          |                        |                  |
| pulsed 293-CIITA cells    | times background          |                     |          |                        |                  |
| TCR expression2           | FACS analysis of the      | PBL, >10%           |          |                        |                  |
| transduced cells          |                           |                     |          |                        |                  |
| Microbiological           | gram stain1,3,            | no micro-organisms  |          |                        |                  |
| studies                   | seen                      |                     |          |                        |                  |
| aerobic culture3,4        | no growth                 |                     |          |                        |                  |
| fungal culture3,4         | no growth                 |                     |          |                        |                  |
| anaerobic culture3,4      | no growth                 |                     |          |                        |                  |
| mycoplasma test5          | negative                  |                     |          |                        |                  |
| Endotoxin                 | limulus assay1            | ≤ 5 E.U./kg         |          |                        |                  |
| RCR                       | S+L- Assay4 RCR-PCR6      | negative            |          |                        |                  |  
Prepared by: _______________________________________ Date: ____________________
QC sign-off: _______________________________________ Date: ____________________
Qualified Clinical or Laboratory Supervisor