appendix 2
appendix 1 '9(56((9(1762&&855112)37(17675(7('7+ aldesleukin (n=525)1

| Expected IL-2 Toxicities and their Management                                                               |               |                                                                                                                                                 |                                                                  |                   |
|-------------------------------------------------------------------------------------------------------------|---------------|-------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------|-------------------|
| Expected toxicity                                                                                           | Expected      | Supportive                                                                                                                                      | Stop Cycle*                                                      | Stop Treatment ** |
| grade                                                                                                       | Measures      |                                                                                                                                                 |                                                                  |                   |
| 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  simultaneously                       | No                |
| Hyperbilirubinemia                                                                                          | 3 or 4        | Observation                                                                                                                                     | If other toxicities  occur  simultaneously                       | No                |
| Anemia                                                                                                      | 3 or 4        | Transfusion with                                                                                                                                | If uncontrolled                                                  |                   |
| PRBCs                                                                                                       | despite all   |                                                                                                                                                 |                                                                  |                   |
| supportive measures                                                                                         | No            |                                                                                                                                                 |                                                                  |                   |
| Thrombocytopenia                                                                                            | 3 or 4        | Transfusion with                                                                                                                                | If uncontrolled                                                  |                   |
| platelets                                                                                                   | despite all   |                                                                                                                                                 |                                                                  |                   |
| supportive measures                                                                                         | No            |                                                                                                                                                 |                                                                  |                   |
| Edema/Weight gain                                                                                           | 3             | Diuretics prn                                                                                                                                   | No                                                               | No                |
| Hypotension                                                                                                 | 3             | Fluid resuscitation                                                                                                                             | If uncontrolled                                                  |                   |
| Vasopressor support                                                                                         | despite all   |                                                                                                                                                 |                                                                  |                   |
| supportive measures                                                                                         | No            |                                                                                                                                                 |                                                                  |                   |
| 11-C-0013                                                                                                   | 65            |                                                                                                                                                 |                                                                  |                   |  
| Dyspnea                                                                                                                           | 3 or 4                             | Oxygen or ventilatory                      | If requires                  | No                  |
|-----------------------------------------------------------------------------------------------------------------------------------|------------------------------------|--------------------------------------------|------------------------------|---------------------|
| support                                                                                                                           | ventilatory support                |                                            |                              |                     |
| Oliguria                                                                                                                          | 3 or 4                             | Fluid boluses or  dopamine at renal  doses | If uncontrolled  despite all |                     |
| supportive measures                                                                                                               | No                                 |                                            |                              |                     |
| 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 all |                     |
| supportive measures                                                                                                               | No                                 |                                            |                              |                     |
| 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 all       |                                            |                              |                     |
| supportive measures                                                                                                               | No                                 |                                            |                              |                     |
| Elevated Troponin                                                                                                                 | 3 or 4                             | Observation                                | Yes                          | If changes in LV    |
| levels                                                                                                                            | 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 have not |
| transaminases                                                                                                                     | liver metastases                   | improved to baseline  by next dose         |                              |                     |
| Hyperbilirubinemia                                                                                                                | 3 or 4                             | Observation                                | For grade 4 without          | If changes have not |
| liver metastases                                                                                                                  | improved to baseline  by next dose |                                            |                              |                     |
| Electrolyte                                                                                                                       | 3 or 4                             | Electrolyte                                | If uncontrolled              |                     |
| imbalances                                                                                                                        | replacement                        | despite all                                |                              |                     |
| supportive measures                                                                                                               | No                                 |                                            |                              |                     |
| 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. |                                    |                                            |                              |                     |
appendix 2
appendix 3 interleukin-2 toxicities observed

| 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  | 128   | 32    | e   | 19  | 214  | 666   | 652* |
| 236                                                 | 85    | 210 | 35    | 30    | 348 | 95  | 1039 |       |      |
| Number of Courses                                   | 75    | 16  | 68    | 8     | 191 | 33  | 39   |       |      |
| Chills                                              | 8     |     |       |       |     |     |      |       |      |
| Pruntus                                             | 53    | 9.  | 26    | 2     | 2   | 82  | 6    | 180   |      |
| Necrosis                                            | 3     | l   | 2     | l     | l   | l   | s    |       |      |
| Anaphylaxis                                         | il    | i   | al    | l     |     | l   |      |       |      |
| Mucositis (requiring liquid diet)                   | 6     | I   | 7     | 2     | 12  | 2   | 30   |       |      |
| l                                                   |       |     |       |       |     |     |      |       |      |
| Alimentation not possible                           | l     | l   | l     | l     | 2.2 | l   | 4    |       |      |
| 162                                                 | 42    | 17  | 20    | 263   | 666 |     |      |       |      |
| Nausea and vomiting                                 | 14    | 48  |       |       |     |     |      |       |      |
| Diarrhea                                            | 144   | 38  | 98    | 15    | 13  | 250 | 38   | 596   |      |
| Hyperbilirubinemia (maximum/mg %)                   | 97    |     |       |       |     |     |      |       |      |
| 2.1-6.0                                             | 126   | 49  | 21    | 18    | 190 | 46  | 547  |       |      |
| 6.1-10.0                                            | 49    | 3   | 12    | 8     | 9   | 72  | 26   | 179   |      |
| 10.1+                                               | 26    | i   | 4     | 3     | l   | 40  | 8    | 83    |      |
| Oliguria                                            |       |     |       |       |     |     |      |       |      |
| <80 ml/8 hours                                      | 81    | 37  | 67    | 14    | 9   | 114 | 25   | 347   |      |
| <240 ml/24 hours                                    | 19    | 2   | 3     | i     | 112 | s   | 42   |       |      |
| Weight gain (% body weight)                         |       |     |       |       |     |     |      |       |      |
| 0.0-5.0                                             | 106   | 23  | 65    | 8     | 9   | 17  | 49   | 377   |      |
| 5.1-10.0                                            | 78    | 41  | 11    | 22222 | 10  | 148 | 26   | 436   |      |
| 10.1-15.0                                           | 43    | 17  | 26    | 3     | 9   | 62  | 15   | 175   |      |
| 15.1-20.0                                           | 7     | 3   | 8     | i     | 1   | 15  | 3    | 38    |      |
| 20.1+                                               | 2     | I   | l     | l     | 6   | 2   | 13   |       |      |
| Elevated creatinine (maximum/mg %)                  | 148   | 43  | 121   | 20    | 14  | 237 | 54   | 637   |      |
| 2.1-6.0                                             |       |     |       |       |     |     |      |       |      |
| 6.1-10.0                                            | 21    | -   | 14    | 3     | l   | 34  | 12   | 85    |      |
| 10.1+                                               | s     |     | l     | l     | l   | 2   | l    | 10    |      |
| 2                                                   |       |     |       |       |     |     |      |       |      |
| Hematuria (gross)                                   | l     | l   | l     |       | l   | l   | 2    |       |      |
| Edema (symptomatic nerve or vessel                  |       |     |       |       |     |     |      |       |      |
| compression)                                        | 4     | l   | 6     | l     | l   | 7   | 17   |       |      |
| l                                                   |       |     |       |       |     |     |      |       |      |
| Tissue ischemia                                     | l     | l   | l     | i     | l   | 2   |      |       |      |
| l                                                   | l     |     |       |       |     |     |      |       |      |
| Resp. distress:                                     |       |     |       |       |     |     |      |       |      |
| not intubated.                                      | 17    | i   | 9     | 4     | l   | 28  | 7    | 67.67 |      |
| intubated                                           | 15    |     | 6     | 3     | 12  | s   | 41   |       |      |
| Bronchospasm                                        | 2     | l   | 2     | l     | l   | 4   |      | 9     |      |
| Pleural effusion (requiring                         |       |     |       |       |     |     |      |       |      |
| thoracentesis)                                      | 4     | i   | l     | 2     | 8   | l   | 17   |       |      |
| l                                                   |       |     |       |       |     |     |      |       |      |
| 2                                                   | 22    |     |       |       |     |     |      |       |      |
| Somnolence                                          | 29    | 6   | 2     | 45    | 8   | 14  |      |       |      |
| Coma                                                | 9     | l   | 8     | 2     | 8   | s   | 33   |       |      |
| Disorientation                                      | 52    | 3   | 50    | 7     | 4   | 89  | 10   | 215   |      |
| Hypotension (requiring pressors)                    | 19    | 16  | 40    | 17    | 12  | 259 | 508  |       |      |
| 45                                                  |       |     |       |       |     |     |      |       |      |
| Angina                                              | s     | I   | 8     | l     | l   | 8   |      | 22    |      |
| Myocardial infarction                               | 4     | 1   | l     | l     | 1   | l   | 16   |       |      |
| Arrythmias                                          | 15    | 2   | 13    | 3     | l   | 39  | 6    | 78    |      |
| Anemia requiring transfusion (number                |       |     |       |       |     |     |      |       |      |
| units transfused)                                   |       |     |       |       |     |     |      |       |      |
| 1-15                                                | 77    | 16  | 53    | 9     | 6   | 176 | 40   | 37    |      |
| 6-10                                                | 22    | I   | S     | 3     | 2   | 53  | 9    | 95    |      |
| 1-15                                                | 4     | l   | 15    |       |     |     |      |       |      |
| l                                                   | l     | l   | 4     | 24    |     |     |      |       |      |
| 16+                                                 | l     | l   | l     | l     | l   | 11  | l    | 14    |      |
| Thrombocytopenia (minimum/mm')                      |       |     |       |       |     |     |      |       |      |
| <20,000                                             | 28    | i   | 2     | 4     | 71  |     |      |       |      |
| 1, 116                                              | 19    | 131 |       |       |     |     |      |       |      |
| 20,001-60,000                                       | 82    | 11  | 62    | 14    | 12  | 150 | 30   | 361   |      |
| 60,001-100,000                                      | 53    | 36  | 76    | 11    | 8   | 79  | 22.  | 285   |      |
| 13                                                  | 7     |     |       |       |     |     |      |       |      |
| Cntral line sepsis                                  | l     | l   | 4     | 36    | 2   | 63  |      |       |      |
| Death                                               | 4     | l   | l     | l     | 3   | 2   | 10   |       |      |
| * Eleven patients are in two protocols.             |       |     |       |       |     |     |      |       |      |
certificate of analysis infused t
appendix 3 interleukin-2 toxicities observed

| Tests performed on final product: Test Method   | Limits                   | Result                                            | Initials/ Date   |
|-------------------------------------------------|--------------------------|---------------------------------------------------|------------------|
| Cell viability1                                 | trypan blue exclusion    | >70%                                              |                  |
| Total viable cell                               | visual microscopic count | Between 106 and                                   |                  |
| number1                                         | 5 x 1010 cells           |                                                   |                  |
| Identity                                        | FACs                     | > 80 % CD3+CD8+  after transduction on  REP cells |                  |
| Tumor reactivity2                               | J-IFN release vs.        | >200 pg/ml and > 2                                |                  |
| VEGFR2 cell line                                | times background         |                                                   |                  |
| CAR expression2                                 | FACS analysis of the     | PBL, >30%                                         |                  |
| 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              | negative                                          |                  |
| RCR-PCR6                                        |                          |                                                   |                  |  
Date of preparation of final product: Patient:
1 Performed on sample of the final product immediately prior to infusion. Results are available at the time of infusion. 2 Performed 2-10 post transduction. Results are available at the time of infusion.  
3 Performed 2-4 days prior to infusion. Results are available at the time of infusion but may not be definitive.  
4 Sample collected from the final product prior to infusion. Results will not be available before cells are infused into the patient. 5 Performed 2-10 days prior to infusion. Results are available at the time of infusion.  
6 Performed on sample approximately 1-4 days prior to infusion. Results are available at the time of infusion.  
Prepared by: _________________________________________ Date: ____________________