Systemic IL-2 therapy of cancer 82 81 57 46 5 7 83 Conclusion The development of systemic IL-2 therapy was a break-through in cancer immunotherapy. We supposed that the drawbacks of systemic IL-2 application might be overcome by local IL-2 application. Effectiveness of local versus systemic IL-2 therapy Subject The therapeutic effectiveness of local versus systemic IL-2 application. Data 86 94 10 . 2 68 33 55 23 56 61 13 Conclusion The data show that local IL-2 therapy and in particular intratumoral IL-2 application is more effective than systemic IL-2 therapy. Local IL-2 therapy leads to systemic therapeutic effects even curing metastatic disease Subject Obviously a major problem of cancer therapy is inducing regression of metastases. Immunotherapy of cancer is an attractive concept, as systemic immunity may indeed cure metastases. Consequently, many groups have concentrated on the systemic therapeutic effects of local IL-2 therapy. Data 67 67 95 29 96 56 55 70 Conclusion 68 96 1 2 Subject 32 Table 1 Successful therapeutic effects of local IL-2 application on transplanted tumors: results published by other groups Tumors Species Route of IL-2 application Therapeutic effect References Carcinomas Mammary carcinomas Mouse Peritumoral + 94 95 Transitional cell carcinoma Mouse Intratumoral + 87 Lung carcinoma Mouse Intratumoral ++ 33 Prostate carcinoma Rat Intratumoral + 50 Sarcomas MC-induced sarcomas Mouse Peritumoral + 16 18 HeJ fibrosarcoma Mouse Peritumoral ++ 10 MCA106 sarcoma Mouse Peritumoral + 2 Lymphoma RBL5 lymphoma Mouse Peritumoral + 10 Miscellaneous Myeloma X5563 Mouse Local site ++ 69 Melanoma Mouse Tumor site ++ 86 Friend leukemia Mouse Peritumoral + 10 HPV associated tumor Mouse Tumor site + 21 We have included data of all papers that we have found on therapeutic effects of local application of free IL-2 to transplanted cancer in animals 1 + ++ Table 2 Therapeutic effect of local IL-2 application on transplanted tumors: results from our group Tumor Organ /type Species Predictive model Route of application Therapeutic effect References Carcinomas Line 10 Liver Guinea pig + Intratumoral + 6 72 M8013 Breast Mouse    Peritumoral + 58 MOT Teratoma Mouse   Intratumoral - 14 MC-ASN Breast Mouse + Peritumoral ± 73 MC-BC Breast Mouse + Peritumoral ± 73 MC38 Colon Mouse + Peritumoral + 64 5D04 Stomach Mouse   Intratumoral -   VX2 carcinoma Head and Neck Rabbit + Peritumoral + 96 Recently arisen carcinomas X5 Breast Mouse   Intratumoral ± 42 X6 Breast Mouse   Intratumoral ± 42 X9 Breast Mouse   Intratumoral ± 42 Sarcoma Mecho  Fibrosarcoma Mouse   Intratumoral +   Lymphomas SL2 Lymphoma Mouse + Intratumoral ++ 12 67 68 70 L5178Y Lymphoma Mouse   Intratumoral ++ 67 L1210 Lymphoma Mouse   Intratumoral +   RBL5 Lymphoma Mouse   Intratumoral +   EL4 Lymphoma Mouse   Intratumoral −   Miscellaneous TLX9 Thymoma Mouse   Intratumoral −   P815 Mastocytoma Mouse + Intratumoral ++ 68 1 ± + ++ 68 Data 18 16 18 67 9  12 37 1 2 1 2 6 33 42 50 58 64 72 73 87 94 96 10 16 18 86 69 10 66 67 10 68 21 2 27 14 27 27 1 2 32 2 Conclusion 67 2 3 Subject Table 3 Therapeutic effect of local IL-2 application veterinary cancer patients Type of cancer Host Therapeutic effect References Bovine ocular squamous cell carcinoma Cattle ++ 30 31 84 89 90 Vulval papilloma and carcinoma complex Cattle + 51 Sarcoids Horses + 88 Fibrosarcoma Dogs + 100 This Table summarizes to our knowledge all published studies on local application of free IL-2 in veterinary cancer patients + ++ Data 3 Bovine Ocular Squamous Cell Carcinoma (BOSCC) BOSCC originates in the cornea, the third eyelid (membrana nictitans), the lower or the upper eyelid. Ultimately the tumor covers the whole eye. It also metastasizes to the draining lymph nodes. This tumor occurs frequently in tropical countries with intense solar radiation, particularly at high altitudes. BOSCC is for various reasons a very useful veterinary tumor model: The tumor is readily visible and can be directly treated with peritumoral or intratumoral IL-2 injection in field studies. 84 31 86 2 3 4 5 5 6 6 89 30 90 31 Bovine Vulval Papilloma and Carcinoma Complex (BVPCC) 19 51 19 51 Twenty three papillomas and carcinomas of the bovine vulva were treated with local IL-2 therapy. Sixteen partial remissions and three complete remissions add to a tumor reduction in 83% of the treated cows [Stewart et al. to be published]. Remissions were striking in papillomas with a massive lymphocytic infiltrate in particular in those epithelial areas that showed marked dysplasia or (pre-)malignant changes. Sarcoids 88 Fibrosarcomas in dogs 100 Conclusion Local IL-2 therapy can be effective against spontaneous veterinary tumors. Local IL-2 application has an enormous economical impact as BOSCC as well as BVPCC occur in about 10% of cattle in Zimbabwe and probably also in other tropical countries. Local IL-2 treatment of BOSCC leads to CR in the majority of the cases, and led to tumor reduction in the majority of BVPCC cases. 68 96 4 Subject Table 4 Therapeutic effect of local IL-2 application on human cancer patients Type of cancer Number of patients CR PR SD PD References Basal cell carcinoma 12 8 3 1 – 59 Bladder carcinoma 6 3 3 – – 79 Bladder carcinoma 5 1 – 4 – 53 Bladder carcinoma 14 3 – 11 – 44 45 Bladder carcinoma 9 9 – – – 41 Bladder carcinoma 10 8 – 2 – 29 Gastro-intestinal cancer 16 – 6 – 10 61 Hepatocellular carcinoma 5 – 1 3 1 85 Lung cancer; pleural effusions 21 7 6 – 8 71 Melanoma 26 5 8 5 8 35 Melanoma 23 15 5 – 3 80 Mesothelioma 21 – 4 7 10 43 Mesothelioma 22 1 11 3 7 5 Mesothelioma 31 1 6 10 14 22 Mesothelioma 1 1 – – – 62 Ovarian carcinoma 35 6 3 7 19 34 Ovarian carcinoma 17 6 3 – 8 91 Neoplastic effusions 14 4 6 – 4 65 Total numbers 288 78 65 53 92   Percentage (%) 100 27 23 18 32   CR PR SD PD Data Basal cell carcinoma 59 Bladder carcinoma 79 53 44 45 40 41 26 29 29 47 26 29 Gastrointestinal tumors 85 61 Melanoma 80 78 Mesothelioma 43 5 22 62 Neoplastic effusions 71 65 22 Ovarian carcinoma 34 91 Renal cell carcinoma (lung metastases) 52 52 36 Quantification of therapeutic data 4 Toxic effect of local IL-2 application 5 41 22 34 43 5 43 6  22 6 6 34 Table 5 Toxic effects of local IL-2 application on human cancer patients Reference  Toxic side effects 59 Local pain, swelling, erythema, in one patient fluelike symptoms 79 No early or late adverse clinical side effects 53 No evidence of side effects 44 45 Toxicity from IL-2 given intravesically was minimal. One patient malaise for 24 h after each treatment. Two patients developed asymptomatic lower urinary tract infections 41 2/9 patients had hematuria after the end of treatment; one patient had fever (grade I), and seven patients had hypotension (grade I-II) 29 No toxic effects 61 Negligible adverse effects 85 Abstract did not contain toxicity data 71 Treatment of pleural effusions of lung cancer was well tolerated 35 Side effects of treatment were minimal 80 Therapy was generally well tolerated; the observed adverse events were mainly of grade 1–2 severity 43 6 5 Intrapleural administration of IL-2 was well tolerated 22 6 6 62 Abstract did not contain toxicity data 34 b 5 2 91 Abstract did not contain cytotoxicity data 65 No important toxicity in 14 patients with neoplastic effusions after intracavitary administration of IL-2 36 a Inhaled IL-2: most common toxicities were cough (40% of cycles) and fatigue (7%). Grade 1 or 2 toxicities  40 a Locoregional perfusion of the bladder with IL-2 is safe 52 a 116 patients. Toxicity associated with exclusive inhalation of IL-2 was local and consisted mainly of cough 93 a Intravesical IL-2 instillation. No evidence of toxicity 97 a Regionally administered IL-2 was well tolerated in patients with advanced squamous cell carcinoma of the head and neck 4 a 4 b Dose–response 1 3 5  6 9 12 1 1 6 9 4 1 55 Fig. 1 4  Conclusions Local IL-2 therapy can be effective against a variety of human tumors. 29 There is no obvious dose–response with regard to therapeutic effects. 3  5 8  6 Subject Table 6 Synergism of local IL-2 therapy with other therapeutic modalities Therapy Tumor Host Therapeutic effect References Surgery   Fibrosarcoma Dog a 100 Radiotherapy   Lymphoma Mouse P a 38 58   Nasopharyngeal carcinoma  Man a 55 Cytokine therapy Interleukin-1 Friend leukemia Mouse  Synergistic effect with IL-2, 60% survival 10 Chemotherapy Cyclophosphamide Melanoma  Mouse a 86 Cis-platinum Terato carcinoma Mouse a 14 Doxorubicin M109 adenocarcinoma Mouse Synergistic effect with long term survivors 20 Ifosfamide TC1 Mouse b 54 Cis-platinum Sarcoids Horse c 77 Imiquinod Melanoma metastases Man  40.7% OR 48 a b c Data Surgery 100 IL-2 instillation in the bladder to treat bladder tumors seems only effective after a preceeding TUR (see above). Radiotherapy 38 58 55 55 Cytokine therapy 10 Chemotherapy 35 86 14 88 54 20 48 Conclusion 35 Mechanism of tumor regression due to local IL-2 application  Original hypothesis on the mechanism of IL-2 in tumor destruction 15 81 82 9 67 10 70 70 68 60 60 an almost immediate marked edema due to leakage of the local blood vessels; a later and more complex reaction consisting of the induction of angiogenesis, a macrophage reaction, migration of the infiltrate into the seminecrotic tissue and finally clearance of tissue in combination with granulomatous processes. Some hemodynamic features in tumors 98 26 49 25 8 24 60 64 2 8 67 68 73 91 Fig. 2 Mechanism of tumor regression caused by local IL-2 application of cancer  67 68 6 68 96 2 56 7 68 96 37 67 69 Slow tumor regression of less vascularized tumors 30 84 88 60 Of course both processes (edema and leukocyte infiltration after neoangiogenesis) are always present as a result of local IL-2 application. But in fast-regression models edema is more prevailing, in slow-regression models leukocyte and particularly macrophage infiltration dominate. 8 Obviously IL-2 may stimulate the existing inflammation as often present in tumors and hence attracts more macrophages and inflammatory cells, and as a consequence intensifies the already existing cellular response to the tumor. Usually, there is in the perivascular zones a marked increase of varied types of inflammatory cells. 14 88 38 6 96 6 Tumor tolerance and local IL-2 In the previous sections histopathological techniques were used to study the mechanism of IL-2 induced tumor regression. In this section we will also pay some attention to immunological data. 1 3 75 77 99 76 74 3 4 11 39 70 63 92 69 70 Conclusions Local IL-2 application seems to induce severe vascular leakage in well-vascularized and fast growing tumors. This leakage in fast growing tumors induces a massive hemorrhagic necrosis which results in early clearance of the tumor tissue. In less-vascular tumor tissue the edema formation is more limited. Neoangiogenesis allows the arrival of especially macrophages that move to the tumor site. This leads to tumor cell killing and a specific immune reaction, resulting in tumor regression. The character of this immune reaction probably depends on the different types of tumor-associated antigens present in the seminecrotic tumor debris. According to our views the primary effects of local IL-2 application to a tumor are the vascular phenomena followed by a host of complex histological events clearing the tumor necrosis. The immune reactivity seems to be a secondary and presumably an indirect effect. Of course, this is an analysis at the histopathological level. The whole process is far more complicated as immune regulatory events––including cells and cytokines are involved. Characteristics of local IL-2 therapy 67 68 96 67 68 31 67 68 88 6 67 68 96 3 4 55 68 28 67 68 73 91 Most of the tumors that well respond to local IL-2 treatment are those with an already (pre-)existing peritumoral leukocytic infiltrate. 6 96 24 67 68 30 31 88 6 5 Local IL-2 does not hamper or interfere with the standard oncotherapy. The local IL-2 therapy findings suggest to revisit our views on the relation between local and systemic oncotherapy at least as far as IL-2 therapy concerns Systemic chemotherapy/hormone therapy, and later immunotherapy, were initially particularly reserved for patients in which adequate tumor treatment by surgery and radiotherapy was not possible. In most of these cases the tumor was inoperable or disseminated and often the patient was in the terminal phase of the disease. Now with modern therapeutic regimes the indications of systemic treatment have been extended, whereas local tumor treatment is becoming rare. Data described in this paper show that cancer treatment with local IL-2 application can lead to cure of metastases. We stress that there are good reasons to consider IL-2 tumor treatment also in early cancer. Surgical treatment remains the golden standard in malignant tumors. Local IL-2 therapy may be considered in local tumors if these tumors can not be resected completely. Occasionally a previously inoperable lesion might become fit for surgical interventions due to the reduction of the tumor size. In some cases local IL-2 application may be considered as an adjunct to the standard treatment particularly if recurrences are expected. An example of the latter is local IL-2 treatment in TUR-treated bladder tumors. Local IL-2 therapy may also be used as an adjunct to treat a primary tumor showing metastases. In advanced tumor cases local IL-2 treatment of the primary tumor may induce a specific immune response and might also contribute to cure or decrease tumor size and sometimes also may have a positive effect on the metastases. IL-2 does not interfere with the standard oncotherapy and might be an useful adjunct to diminish suffering and expand lifespan. Dose at the tumor site Reduced side effects No immunologic overflow feed-back Reduced costs of locally applied low doses Local IL-2 application: doses and duration of the treatment 28 67 64 28 30 6  6  6  6  6  6  28 56 Website http://cancerimmunotherapy.net/ We provide information targeted on medical professionals. Readers are invited to co-operation. Please reach us at w.denotter@uu.nl.