Use Of Tumor-infiltrating Lymphocytes Research Articles

Insight into the significance of CD8+ tumor-infiltrating lymphocytes in squamous cell lung cancer.

Although there are great expectations regarding the use of tumor-infiltrating lymphocytes (TILs) to predict effects of immunotherapies and prognosis, knowledge about TILs remains insufficient for clinical application. We objectively investigated the prognostic significance of tumor-infiltrating CD8 + lymphocytes (CD8 + TILs) in squamous cell lung cancer (SQ-LC). Among patients who underwent surgical resection of SQ-LC in 2011-2017, 100 patients with pathological stage IA3-III were immunohistochemically studied to evaluate CD8 + TILs in the tumor stroma and parenchyma. The impact of CD8 + TILs on relapse-free survival was analyzed using a Kaplan-Meier survival analysis and multivariate analyses using Fine-Gray and Cox proportional hazards models. The multivariate analysis showed that large and small numbers, but not intermediate numbers, of CD8 + TILs in the tumor stroma may be related to a more favorable prognosis (small vs. intermediate: HR, 0.64; 95% CI: 0.29-1.41, p = 0.27; large vs. intermediate: HR, 0.48; 95% CI: 0.21-1.09, p = 0.08). In contrast, a large number of CD8 + TILs in the tumor parenchyma was associated with a poor prognosis (HR, 2.60; 95% CI: 0.91-7.42, p = 0.075). An exploratory analysis showed a potentially strong association between an extremely large number of CD8 + TILs in the tumor parenchyma and a poor prognosis, even with a large number of CD8 + TILs in the tumor stroma. Our study provided partial but important information on the significance of CD8 + TILs in SQ-LC. To use CD8 + TILs as biomarkers, a better understanding of CD8 + TILs as well as other important components in the tumor microenvironment and the inflammatory phenotypes they form may be needed.

Expression of Programmed Cell Death Ligand-1 and Mismatch Repair Status in Endometrial Carcinomas.

Programmed death ligand-1 (PD-L1) is a co-regulatory molecule that suppresses local immunity, and mismatch repair (MMR) deficiency (dMMR) is reported to influence the response to anti-PD-L1-targeted therapy. This study was conducted to find the PD-L1 status, the occurrence of dMMR in endometrial carcinomas, and the association between them. The study included 35 resected specimens of endometrial carcinomas represented on formalin-fixed paraffin-embedded sections from January 2016 to July 2020. The clinicopathologic information including patient age, tumor histologic type, grade, stage, lymphovascular invasion, the extent of myometrial invasion, and the percentage of tumor-infiltrating lymphocytes (TILs) were obtained in all cases. The expression of PD-L1 and MMR antibodies including mutS homolog 2 (MSH-2), MSH-6, mutL homolog 1 (MLH-1) and MLH-3, and postmeiotic segregation 2 were assessed using immunohistochemistry. The statistical analysis was done using the Statistical Package for the Social Sciences (SPSS) version 26. PD-L1 expression was noted in 48.6% of the cases in tumor cells and 65.7% of the cases in TILs and MMR was deficient in 28.6% of endometrial carcinomas. A statistically significant relation was noted between dMMR and TILs, PD-L1 expression in tumor cells and TILs, PD-L1 expression in tumor cells, and extent of myometrial invasion. Although there was no statistically significant association between MMR status and PD-L1 expression in tumor cells or TILs, 60% of patients with dMMR were PD-L1 positive. Sixty percent of dMMR cases showed PD-L1 expression in tumor cells. We conclude, ECs that are MMR deficient might get better response to anti-PD-L1 therapy. This study also revealed the prognostic use of TILs in PD-L1-expressed tumors.

Ex vivo isolation, expansion and bioengineering of CCR7+CD95-/or CD62L+CD45RA+ tumor infiltrating lymphocytes from acute myeloid leukemia patients' bone marrow.

T cell based immunotherapies can be applicable to acute myeloid leukemia (AML). Therefore, the selection of optimal T cells, cell manufacturing, and therapeutic T cell engineering are essential for the development of effective adoptive T cell therapies for AML. Autologous tumor-infiltrating lymphocytes (TILs) have been in clinical trials to treat solid malignancies. Herein, we assessed whether TILs can be isolated from the bone marrow (BM) of AML patients, expanded ex vivo and utilized as a novel therapeutic strategy for AML. To this end, firstly we analyzed the immunophenotypes of a series of primary BM samples from AML patients (N = 10) by flow cytometry. We observed a variable amount of CD3+ TILs (range ∼2.3–∼32.6% of mononuclear cells) among BM samples. We then developed a novel protocol that produced a three-log ex vivo expansion of TILs isolated from AML patient BM (N = 10) and peripheral blood (PB) (N = 10), including from patients with a low number of CD3+ T cells, within 3, 4 weeks. Further, we identified previously described naïve T cells (CCR7+CD95-/or CD62L+CD45RA+) in AML BM and PB samples, which seemed to be required for a successful TILs ex vivo expansion. Finally, we showed that the expanded TILs could: (1) cause cytotoxicity to autologous AML blasts ex vivo (90.6% in control without T cell treatment vs. 1.89% in experimental groups with PB derived T cells and 1.77% in experimental groups with BM derived TILs, p < 0.01), (2) be genetically engineered to express CYP27B1 gene, and (3) infiltrate the BM and reside in close proximity to pre-injected autologous AML blasts of engrafted immunodeficiency mice. Altogether, these results provide a rationale for further studies of the therapeutic use of TILs in AML.

High expression of immune checkpoints is associated with the TIL load, mutation rate and patient survival in colorectal cancer.

Adoptive cell therapy with the use of tumor-infiltrating lymphocytes (TILs) is a very promising immunotherapeutic approach for the treatment of patients with colorectal cancer (CRC). However, within the tumor microenvironment, co-inhibitory immune checkpoints can inactivate TILs. The aim of the present study was to examine the association between the TIL load, the mutation rate and the clinical outcome in the immune landscape of patients with CRC. RNA-seq and whole exome seq data of 453 colon adenocarcinomas (COAD) and rectal adenocarcinomas (READ), along with the TIL load and clinicopathological information of each patient, were extracted from the TCGA GDC Data Portal and analyzed computationally. The expression of immune checkpoint molecules was compared between colon cancer and normal tissue. A total of 9 immune-related gene signatures were investigated in CRC. Spearman's correlation analysis was performed to examine the correlation between the TIL load with the expression of each immune checkpoint molecule. Indoleamine 2,3-dioxygenase 1 (IDO1) was found to be significantly overexpressed in CRC, whereas V-domain Ig suppressor of T cell activation (VISTA) and lymphocyte activating 3 (LAG3) were markedly downregulated. A high expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), IDO1, programmed cell death 1 (PD-1) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), tended to be associated with a better overall survival of the patients. In COAD, the TIL load positively correlated with the expression of adenosine A2A receptor (ADORA2A), CTLA-4, hepatitis A virus cellular receptor 2 (HAVCR2), lymphocyte activating 3 (LAG3), programmed death-ligand PD-L1, PD-L2, TIGIT and VISTA, whereas in READ, such positive correlations were noted only between the TIL load and LAG3 or PD-L2. The 'central memory T-cell' and 'exhausted T-cell' gene signatures were significantly lower among the READ tumors. The expression of PD-1, PD-L1, PD-L2, CTLA-4 and IDO1 was significantly higher among COAD patients with a high mutation rate (>34 mutations/Mb) compared to those with a lower rate. Somatic mutations in PD-1, PD-L1, CTLA-4 and other checkpoint molecules did not seem to affect their expression levels. On the whole, the data of the present study highlight the association of immune checkpoint molecules with the TIL load, patient survival and a high mutation rate in CRC. The data corroborate that patients with colon cancer with higher PD1, PD-L1/2, CTLA-4 and IDO1 expression, and a high mutation rate, are the ones who will benefit more from the respective immune checkpoint inhibition therapies.

Nevertheless, They Persisted

Nevertheless, They Persisted

The Current Use of Biomedical Cell Products for Cancer Treatment

Cancer remains one of the leading causes of death. Conventional treatment methods, including radiation and chemotherapy, have limited effectiveness. Therefore, the development of novel approaches to cancer treatment is an urgent challenge. Biomedical cell products (BMCPs) which include adoptive cell therapy (ACT) and dendritic cells vaccines (DCVs) are considered a promising area of research. The aim of the study was to review current ideas about the principles of BMCP therapy, as well as clinical experience with cell-based products used for cancer treatment. The paper summarises the results of clinical use of tumor-infiltrating lymphocytes (TIL-therapy), genetically modified T-cells that express tumour antigen-specific receptors (TCR/CAR T-therapy), as well as DCVs. The use of human immune cells genetically modified ex vivo is a novel and promising approach to cancer treatment. The main analysed ACT approaches which are based on the use of genetically modified T-lymphocytes have some benefits and drawbacks. The paper discusses the methods of BMCP production, provides data on the effectiveness of ACT and DCVs. It pays special attention to safety concerns associated with each treatment method, as well as to other factors limiting their clinical use. It is expected that the main areas of further research will be aimed at increasing BMCP efficacy and reducing adverse reactions.

Use of Tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer.

BackgroundEribulin mesylate (eribulin) is currently indicated for treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress epithelial-mesenchymal transition (EMT) of cancer cells. On the other hand, Tumor-infiltrating lymphocytes (TILs), which are considered indicators of immune response monitoring, have been reported as prognostic factors and predictors of therapeutic efficacy. We thought that eribulin, which has an EMT-inhibiting mechanism, may produce an antitumor effect by improving the immune microenvironment, and in this study investigated the effects of breast cancer eribulin chemotherapy on the immune microenvironment with TILs as a marker.MethodsTILs was evaluated in 52 patients with MBC who underwent chemotherapy with eribulin. The correlation between TILs evaluated according to the standard method, and prognosis, including the efficacy of eribulin chemotherapy, was investigated retrospectively.ResultsOf the 52 MBC patients, 29 (55.8%) were in the high TILs group and 23 (44.2%) were in the low TILs group. The high TILs group included significantly more triple-negative breast cancer (TNBC) (p = 0.008) than the low TILs group. In an analysis of outcomes, TNBC patients in the high TILs group had significantly longer disease-free survival than TNBC patients in the low TILs group (p = 0.033, log-rank), but no significant differences were seen in all breast cancer patients (p = 0.489, log-rank) or in non-TNBC patients (p = 0.878, log-rank). In a multivariate analysis of recurrence in TNBC patients, being in the high TILs group was again an independent factor for a good outcome (p = 0.031, HR = 0.063).ConclusionThe results of this study suggest that TILs may be useful as a predictive marker of the therapeutic effect of eribulin chemotherapy in TNBC.

Tumor-Infiltrating Lymphocytes and Breast Cancer: Are Immune Checkpoint Inhibitors Ready for Prime Time in Breast Cancer?

SummaryIn recent years, results obtained from different studies with large cohorts have revealed a bond between the presence of extensive lymphocytic infiltration and favourable prognostic associations in the early-stage of breast cancer (BC) and high response rates to neoadjuvant chemotherapy. Examiners used tumors from large cohorts of patients who took part in randomized neoadjuvant and adjuvant clinical trials. The importance of tumor infiltrating lymphocytes (TILs) appears to be subtype-specific and varies depending on the histological characteristics of the tumor. TILs have proven to be a good prognostic marker, but only in highly proliferative breast tumors such as triple negative breast tumors (TNBC) or HER 2 positive BC.In the era when standard, well-known, prognostic and predictive biomarkers are ever changing and the use of molecular profiling analyses are increasing, we are looking for techniques to improve our understanding of tumor biology and improve patient outcome. The relevance of TILs cannot be ignored but needs to be properly evaluated in larger prospective studies which must encompass the parameters set out in previous studies. The use of TILs as prognostic biomarkers in early breast cancer may represent a new dawn, and use of immunotherapy, especially immune checkpoint inhibitors, probably is the future for the breast cancer but it is not yet ready for prime time.

Interobserver Agreement Between Pathologists Assessing Tumor-Infiltrating Lymphocytes (TILs) in Breast Cancer Using Methodology Proposed by the International TILs Working Group.

The presence of tumor-infiltrating lymphocytes (TILs) in breast tumors is prognostic and predictive, suggesting that TILs may be an important biomarker. Recently, an international TILs working group formulated consensus recommendations for TIL evaluation. The current study was performed to determine interobserver agreement using that methodology. Tumor-infiltrating lymphocytes were assessed on a single hematoxylin and eosin (H&E)-stained slide obtained from the core biopsy of 75 triple-negative breast cancers. Four pathologists independently reviewed each slide and evaluated stromal TILs (sTILs) and intratumoral TIL (iTILs). The kappa statistic was used to estimate interobserver agreement for identification of sTILs, and the intraclass correlation coefficient (ICC) was used to estimate the agreement among observers for iTILs. Cases with poor agreement were reviewed to identify pathologic factors that may contribute to the lack of agreement. The kappa statistic for sTIL evaluation was 0.57 (standard error, 0.04). For iTILs, the ICC calculated to determine internal consistency within raters was 0.65 (95% confidence interval [CI] 0.56-0.74; p<0.0001), and the ICC calculated to determine agreement among raters was 0.62 (95% CI 0.50-0.72; p<0.0001). In 10 cases (13%), there was not agreement between three of four pathologists. The pathologic features contributing to difficulty in TIL enumeration included marked individual tumor cell necrosis or apoptosis, the presence of reactive plasma cells mimicking tumor cells, plasmatoid tumor cells, and accurate quantification of TILs in specimens with focal areas of heavy immune infiltrate. Acceptable agreement in TIL enumeration was observed, suggesting that the proposed methodology can be used to facilitate the use of TILs as a biomarker in research and clinical trial settings.

Endogenous T-Cell Therapy: Clinical Experience.

Adoptive cellular therapy represents a robust means of augmenting the tumor-reactive effector population in patients with cancer by adoptive transfer of ex vivo expanded T cells. Three approaches have been developed to achieve this goal: the use of tumor-infiltrating lymphocytes or tumor-infiltrating lymphocytess extracted from patient biopsy material; the redirected engineering of lymphocytes using vectors expressing a chimeric antigen receptor and T-cell receptor; and third, the isolation and expansion of often low-frequency endogenous T cells (ETCs) reactive to tumor antigens from the peripheral blood of patients. This last form of adoptive transfer of T cells, known as ETC therapy, requires specialized methods to isolate and expand from peripheral blood the very low-frequency tumor-reactive T cells, methods that have been developed over the last 2 decades, to the point where such an approach may be broadly applicable not only for the treatment of melanoma but also for that of other solid tumor malignancies. One compelling feature of ETC is the ability to rapidly deploy clinical trials following identification of a tumor-associated target epitope, a feature that may be exploited to develop personalized antigen-specific T-cell therapy for patients with almost any solid tumor. With a well-validated antigen discovery pipeline in place, clinical studies combining ETC with agents that modulate the immune microenvironment can be developed that will transform ETC into a feasible treatment modality.

Current Issues and Clinical Evidence in Tumor-Infiltrating Lymphocytes in Breast Cancer.

With the advance in personalized therapeutic strategies in patients with breast cancer, there is an increasing need for biomarker-guided therapy. Although the immunogenicity of breast cancer has not been strongly considered in research or practice, tumor-infiltrating lymphocytes (TILs) are emerging as biomarkers mediating tumor response to treatments. Earlier studies have provided evidence that the level of TILs has prognostic value and the potential for predictive value, particularly in triple-negative and human epidermal growth factor receptor 2–positive breast cancer. Moreover, the level of TILs has been associated with treatment outcome in patients undergoing neoadjuvant chemotherapy. To date, no standardized methodology for measuring TILs has been established. In this article, we review current issues and clinical evidence for the use of TILs in breast cancer.

Induced pluripotent stem cells: challenges and opportunities for cancer immunotherapy.

Despite recent advances in cancer treatment over the past 30 years, therapeutic options remain limited and do not always offer a cure for malignancy. Given that tumor-associated antigens (TAA) are, by definition, self-proteins, the need to productively engage autoreactive T cells remains at the heart of strategies for cancer immunotherapy. These have traditionally focused on the administration of autologous monocyte-derived dendritic cells (moDC) pulsed with TAA, or the ex vivo expansion and adoptive transfer of tumor-infiltrating lymphocytes (TIL) as a source of TAA-specific cytotoxic T cells (CTL). Although such approaches have shown some efficacy, success has been limited by the poor capacity of moDC to cross present exogenous TAA to the CD8+ T-cell repertoire and the potential for exhaustion of CTL expanded ex vivo. Recent advances in induced pluripotency offer opportunities to generate patient-specific stem cell lines with the potential to differentiate in vitro into cell types whose properties may help address these issues. Here, we review recent success in the differentiation of NK cells from human induced pluripotent stem (iPS) cells as well as minor subsets of dendritic cells (DCs) with therapeutic potential, including CD141+XCR1+ DC, capable of cross presenting TAA to naïve CD8+ T cells. Furthermore, we review recent progress in the use of TIL as the starting material for the derivation of iPSC lines, thereby capturing their antigen specificity in a self-renewing stem cell line, from which potentially unlimited numbers of naïve TAA-specific T cells may be differentiated, free of the risks of exhaustion.

Tumor-Infiltrating Lymphocytes and Interleukin-2: Dose and Schedules of Administration in the Treatment of Metastatic Cancer

The potential for therapeutic use of tumor-infiltrating lymphocytes (TIL), as adoptive cellular therapy has been touted for many years with some encouraging reports in patients with metastatic melanoma. We previously described methodologies for TIL production and phenotypic characterization of TIL generated in our laboratory between 1991 and 1995 in semipermeable bags and between 1996 and 2000 in bioreactors. Patients treated in the earlier era were to have received a hybrid bolus and a 12-hour continuous infusion of interleukin (IL)-2 (total, 48 MIU), while in the latter era 4 days of interferon- alpha preceded the TIL and IL-2; which was given by a hybrid schedule that included bolus and 72- hour continuous IL-2 (total, 96 MIU). There were 55 patients, including 23 patients with melanoma, 9 patients with renal cell carcinoma, and 8 patients with colorectal cancer. There was only 1 objective tumor response, which was noted in a patient with renal cell carcinoma. The 55 patients who received these products were grouped in cohorts by treatment era, quantity of TIL received, amount of IL-2 intended, and different combinations of TIL and IL-2. There was no difference in survival by production method (treatment era), or amount of IL-2 given with TIL, but 33 patients who received an intermediate or higher dose of TIL (mean = 54.4 x 10(9)) had a median survival of 11.8 months, compared to 6.4 months for 22 patients who received 1 low-dose TIL (mean = 6.48 x 10(9)) (p = 0.059, log rank test). The objective response rate in this heterogeneous group of patients was not encouraging. The data suggest there may be a dose/benefit relationship between the total number of TIL infused and survival.

Immunotherapy with the use of tumor-infiltrating lymphocytes and interleukin-2 as adjuvant treatment in stage III non-small-cell lung cancer: A pilot study: Ratto GB, Melioli G, Zino P, Mereu C, Mirabelli S, Fantino G et al. Istituto Patologia Chirurgica, University of Genoa, Viale Benedetto XV, 16132 Genova. J Thorac Cardiovasc Surg 1995;109:1212–1217

Immunotherapy with the use of tumor-infiltrating lymphocytes and interleukin-2 as adjuvant treatment in stage III non-small-cell lung cancer: A pilot study: Ratto GB, Melioli G, Zino P, Mereu C, Mirabelli S, Fantino G et al. Istituto Patologia Chirurgica, University of Genoa, Viale Benedetto XV, 16132 Genova. J Thorac Cardiovasc Surg 1995;109:1212–1217

Immunotherapy with the use of tumor-infiltrating lymphocytes and interleukin-2 as adjuvant treatment in stage III non-small-cell lung cancer: A pilot study

This study assesses the feasibility and toxicity of adoptive immunotherapy with tumor infiltrating lymphocytes and recombinant interleukin-2 in 29 patients who underwent resection for stage III non-small-cell lung cancer. In five patients cultures yielded no growth of tumor infiltrating lymphocytes. In the remaining 24 patients (stage IIIa, 14 cases; stage IIIb, 10 cases) tumor infiltrating lymphocytes were in vitro expanded from surgically obtained tissue samples, including samples from both the tumor and surrounding lung. A number of tumor infiltrating lymphocytes, ranging from 4 to 70 billion cells, were reinfused intravenously 4 to 6 weeks after operation. Interleukin-2 was administered subcutaneously at escalating doses for 2 weeks and then at reduced doses for 2 to 3 months. Median survival was 14 months, and the 2-year survival was 40%. Three patients remain alive and disease-free at more than 2 years after operation. Two of these patients did not have complete resection at thoracotomy. Multivariate analysis showed no correlation between the factor of incomplete resection and survival. Intrathoracic recurrence without concomitant distant failure was documented in two patients only and none of the patients with incomplete resection (12 cases) had relapse within the thorax. The present experience demonstrates that adoptive immunotherapy may be applied with safety in patients operated on for stage III non-small-cell lung cancer and suggests that it can be useful, notably in patients with locally advanced disease. (J T HORAC C ARDIOVASC S URG 1995;109:1212-7)

Tumor necrosis factor and chemotherapeutic drugs targeted at DNA topoisomerase II for the treatment of genitourinary malignancies.

Recombinant TNF as a single agent for human cancer appears to be of limited value. However, rTNF has synergistic anticancer effects when combined with chemotherapeutic drugs targeted at DNA topoisomerase II. This effect of rTNF has been observed in several in vitro and in vivo tumor models, both in animal and human studies. The mechanism of this interaction appears to involve lesions to the DNA of tumor cells mediated by inhibition of DNA topoisomerase II. The combinations of rTNF plus doxorubicin and rTNF plus etoposide administered systemically are currently under evaluation by clinical trials in patients with advanced cancers. Determination of the efficacy of such combination therapy must await the completion of phase I and II trails. Other routes of administration that might increase the local concentration of rTNF and could be combined with topoisomerase II-targeted drugs include intravesical administration and the use of tumor-infiltrating lymphocytes.

Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report.

Lymphocytes extracted from freshly resected melanomas can be expanded in vitro and can often mediate specific lysis of autologous tumor cells but not allogeneic tumor or autologous normal cells. We treated 20 patients with metastatic melanoma by means of adoptive transfer of these tumor-infiltrating lymphocytes and interleukin-2, after the patients had received a single intravenous dose of cyclophosphamide. Objective regression of the cancer was observed in 9 of 15 patients (60 percent) who had not previously been treated with interleukin-2 and in 2 of 5 patients (40 percent) in whom previous therapy with interleukin-2 had failed. Regression of cancer occurred in the lungs, liver, bone, skin, and subcutaneous sites and lasted from 2 to more than 13 months. Toxic effects of interleukin-2 occurred, although the treatment course was short (five days); these side effects were reversible. It appears that in patients with metastatic melanoma, this experimental treatment regimen can produce higher response rates than those achieved with interleukin-2 administered alone or with lymphokine-activated killer cells. It is too early to determine whether this new form of immunotherapy can improve survival, but further trials seem warranted.

Gene-Transfer Study Approval Awaits More Data

ABSTRACT APPROVAL of the gene-transfer study in cancer patients has been delayed.The proposal was recommended for approval by a National Institutes of Health (NIH) advisory committee, but has been put on hold by James B. Wyngaarden, MD, NIH director, pending submission in writing of further information. Some of this information, now forthcoming, had been withheld because data on preliminary studies had been submitted to peer-reviewed journals.The study involves placing the gene for neomycin-resistance into tumor-infiltrating lymphocytes as a marker. When these cells are injected into the patient, the presence of the marker should enable their fate to be studied over a prolonged period and an improved antitumor regimen could result.The use of tumor-infiltrating lymphocytes as immunotherapy has been studied for two years at the NIH's National Cancer Institute under the overall supervision of Steven A. Rosenberg, MD, chief, Surgery Branch. The patients' tumors are removed and the tumor-infiltrating

NIH conference. New approaches to the immunotherapy of cancer using interleukin-2.

Experimental studies in animals have shown that therapy with high-dose interleukin-2 either alone or in combination with lymphokine-activated killer cells can reduce established pulmonary and hepatic metastases. Based on these experiments, recent clinical trials have shown that therapy with high-dose interleukin-2 alone or in combination with lymphokine-activated killer cells can mediate the regression of established metastatic disease in selected patients with advanced malignancy. Of 221 patients with advanced cancer treated with this immunotherapy, 16 have had a complete regression of all metastatic cancer, and an additional 26 have had a partial regression (greater than 50% reduction) of cancer. Toxicity from treatment was primarily due to increased capillary permeability, which led to fluid extravasation and organ dysfunction. Based on these findings, new approaches are being explored, including the use of tumor-infiltrating lymphocytes and combinations of lymphokines. These studies show that the regression of established growing cancer can be mediated by manipulating the immune system.

A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes.

The adoptive transfer of tumor-infiltrating lymphocytes (TIL) expanded in interleukin-2 (IL-2) to mice bearing micrometastases from various types of tumors showed that TIL are 50 to 100 times more effective in their therapeutic potency than are lymphokine-activated killer (LAK) cells. Therefore the use of TIL was explored for the treatment of mice with large pulmonary and hepatic metastatic tumors that do not respond to LAK cell therapy. Although treatment of animals with TIL alone or cyclophosphamide alone had little impact, these two modalities together mediated the elimination of large metastatic cancer deposits in the liver and lung. The combination of TIL and cyclophosphamide was further potentiated by the simultaneous administration of IL-2. With the combination of cyclophosphamide, TIL, and IL-2, 100% of mice (n = 12) bearing the MC-38 colon adenocarcinoma were cured of advanced hepatic metastases, and up to 50% of mice were cured of advanced pulmonary metastases. Techniques have been developed to isolate TIL from human tumors. These experiments provide a rationale for the use of TIL in the treatment of humans with advanced cancer.