scholarly journals 348 Interleukin 2(IL-2) systems immunology modeling: machine learning for cancer immunotherapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A375-A375
Author(s):  
Jennifer Bone ◽  
Newell Washburn ◽  
Jian Han ◽  
Miranda Steele ◽  
Pranav Murthy ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cancer Immunotherapy ◽  
Language Processing ◽  
Transition Probability ◽  
Interleukin 2 ◽  
Response To Treatment ◽  
High Dose ◽  
Specific Information ◽  
Large Patient ◽  
Systems Immunology

BackgroundClinical outcomes are correlated with aggregate B (BCR) and T cell receptor (TCR) diversity (the adaptome) in several infectious diseases and cancers. Advances in dimer avoidance multiplexed PCR (DAM-PCR) followed by next-generation sequencing (NGS) enable measurements of immune repertoire diversity and clonality, allowing prediction of cancer states and response to treatment. Clonotype-mediated predictions collapse a space of up to 1025 possible CDR3 variable region sequences into descriptors such as whole-sequence diversity. Broad descriptors, however, mask cancer-specific information embedded within clonotype sequences. Deep learning algorithms typically need large patient cohorts to make accurate predictions. We present a statistical model predicting response to IL-2 immunotherapy for small cohorts based on natural language processing (NLP) of CDR3 TCR and BCR clonotypes.MethodsIn a completed Phase 2 trial (NCT01550367), the adaptome of 29 patients with metastatic clear cell renal carcinoma (RCC) treated with high dose (HD) IL-2 and the autophagy inhibitor, hydroxychloroquine (HCQ) were measured from peripheral blood samples by DAM-PCR. All seven TCR and BCR chains were measured at three treatment points (pre-treatment, 14D after HCQ initiation, and following recovery from the first cycle of IL-2 on D15). Outcomes were assessed by assigning two states (responder or non-responder) one year following treatment based on radiographic changes in tumor size. Cancer-specific amino acid motifs from TCR and BCR CDR3 sequences on D15 were mined by counting amino acid pairs and calculating a 400-feature transition probability matrix, scoring the likelihood of a motif belonging to the responder or non-responder cohort.ResultsSeven-chain NLP analysis of CDR3 amino acid motifs at > 90% accuracy for each chain independently predicted patient response to IL-2 by D15 (figure 1). Furthermore, longitudinal monitoring of patient CDR3s across the three timepoints revealed a dichotomy in repertoire orchestration. Responding patients, convincingly, were more likely to demonstrate either a TCR-driven (p<0.01) or a BCR-driven (p<0.001) entropy bias while non-responding patients unanimously showed no significant bias.Abstract 348 Figure 1Classification of nonresponding (Non-Res) and responding (Res) patients based on scoring from Feature Selection Filter and Analysis. ****, p<0.0001; ***, p<0.001; **, p<0.01ConclusionsNLP of both TCR and BCR repertoires can provide early predictions of cancer response to treatment. Furthermore, seven-chain longitudinal monitoring across treatment revealed a surprisingly robust repertoire orchestration in responders that was not observed in non-responders, suggesting that the methodology proposed here can be used to gain new mechanistic insight into the role of repertoire evaluation in cancer immunotherapy.

Correlation between hemodynamic parameters and response to high-dose interleukin-2 in metastatic melanoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 18012-18012
Author(s):  
J. P. Dutcher ◽  
C. Dasanu ◽  
I. Codreanu ◽  
M. Yeddu ◽  
H. Muniswamy ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Statistical Significance ◽  
Interleukin 2 ◽  
Mean Difference ◽  
Mean Blood Pressure ◽  
Response To Treatment ◽  
High Dose ◽  
Separate Analysis ◽  
Significant Drop ◽  
Significant Difference

18012 Background: A direct correlation between the levels of hypotension during IL-2 treatment and response in melanoma has not yet been demonstrated, although both have been correlated with higher IL-2 doses and production of nitric oxide. Methods: A retrospective study analyzed the association between response to IL-2 and systolic, diastolic, mean blood pressure (BP), and heart rate (HR) at baseline and during treatment, by using the t-test. Further, same comparison was performed after BP was corrected for the amount of neosynephrine (neo) utilized during IL-2 treatment (subtracting the raise in BP produced by neo using individual patient coefficients). 22 patients (13 females, 9 males) with a median age of 54 years (range 36–71) received a total of 26 courses of IL-2 (between 2001–2005). Median number of prior treatments was 2.5 (range 0–5). Outcomes were divided in (A) responders (1CR, 3PRs and 4SDs), and (B) non-responders (18PD). Results: When adjusting for the effects of neo, the corrected mean BP during treatment was significantly lower in (A) compared to (B) (52.17 vs 64.34 mmHg, P = 0.018; mean difference −12.17, 95% CI −22.06 to −2.27). Similarly, the decrease in corrected mean blood pressure from baseline was greater in (A) (−34.89 vs −20.67 mmHg, P = 0.003; mean difference −14.22, 95% CI −23.09 to −5.37). A trend towards statistical significance was recorded for the variation in uncorrected mean BP (17.86 vs. 23.22 mmHg, P = 0.085; mean difference −5.36, 95% CI −11.53 to 0.80). Separate analysis demonstrated a significant drop in both systolic (−17.85 mmHg, P = 0.009; 95% −30.77 to −4.91) and diastolic (−12.05 mmHg, P = 0.01; 95% CI −21.02 to −3.07) corrected BP in (A) vs. (B), but no significant difference for either uncorrected parameters. No correlation between response and the HR, number of IL-2 doses or total quantity of neo was observed. Conclusions: Uncorrected variation in mean BP shows a trend towards significance in predicting response to IL-2. However, corrected mean, systolic and diastolic BP correlate closely with response to treatment. Implications of this association may reside in better outcomes for an intensive IL-2 treatment, with aggressive pressor support. A common pathogenetic basis for response to IL-2 and induction of hypotension is possible. No significant financial relationships to disclose.

scholarly journals Randomized Selection Design Trial Evaluating CD8+-Enriched Versus Unselected Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy for Patients With Melanoma

2013 ◽  
Vol 31 (17) ◽  
pp. 2152-2159 ◽  
Author(s):  
Mark E. Dudley ◽  
Colin A. Gross ◽  
Robert P.T. Somerville ◽  
Young Hong ◽  
Nicholas P. Schaub ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Interleukin 2 ◽  
Evaluation Criteria ◽  
Tumor Infiltrating Lymphocytes ◽  
Peripheral Blood Lymphocytes ◽  
Response To Treatment ◽  
High Dose ◽  
Autologous Tumor ◽  
Infiltrating Lymphocytes

Purpose Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. Patients and Methods Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8+-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. Results Thirty-four patients received unselected young TILs with a median of 8.0% CD4+ lymphocytes, and 35 patients received CD8+-enriched TILs with a median of 0.3% CD4+ lymphocytes. One month after TIL infusion, patients who received CD8+-enriched TILs had significantly fewer CD4+ peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8+-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8+-enriched TILs responded. Conclusion A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8+-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.

Cancer Immunotherapy with Interleukin-2—Current Status and Future Developments

2016 ◽  
Vol 12 (02) ◽  
pp. 82
Author(s):  
Shilpa Gupta ◽  
Neeraj Agarwal ◽  
◽  
Keyword(s):  
Combined Treatment ◽  
Interleukin 2 ◽  
Adoptive Cell Transfer ◽  
Response To Treatment ◽  
Current Status ◽  
Term Therapy ◽  
High Dose ◽  
First Line Therapy ◽  
New Therapeutic Approaches ◽  
Number Of Patients

High-dose interleukin-2 (HD IL-2) has been in clinical use in the treatment of metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mM) for over 20 years, and has produced substantial, durable responses in selected patients, resulting in cures in some patients with no ongoing therapy or chronic toxicity. However, use of the drug has remained limited owing to its significant acute toxicities, and the fact that only a minority of selected patients derive a response to treatment. Recent registry data support the use of HD IL-2 as first-line therapy in mRCC and mM, producing major responses for some and thus reducing the requirement for long-term therapy. In addition, an enhanced understanding of the role of IL-2 has led to the development of new therapeutic approaches to maximize the anti-tumor response of IL-2. These strategies include combined treatment with vaccines, antibody treatments to block inhibitory pathways, or adoptive cell transfer of T cells. These data and new approaches have led to continued use of HD IL-2 and may increase the number of patients who derive benefit from this treatment.

Durable Response to Treatment With Combination Radiotherapy and High-dose Interleukin-2 in Metastatic Chromophobe Variant Renal Cell Carcinoma

2016 ◽  
Vol 39 (2) ◽  
pp. 101-103 ◽  
Author(s):  
Joseph Merriman ◽  
Jonathan Tward ◽  
Dan Albertson ◽  
Christopher Dechet ◽  
Neeraj Agarwal
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Interleukin 2 ◽  
Response To Treatment ◽  
High Dose ◽  
Durable Response

Hypothyroidism during immunotherapy with interleukin-2 is associated with antithyroid antibodies and response to treatment.

1993 ◽  
Vol 11 (7) ◽  
pp. 1376-1383 ◽  
Author(s):  
N I Weijl ◽  
D Van der Harst ◽  
A Brand ◽  
Y Kooy ◽  
S Van Luxemburg ◽  
...  
Keyword(s):  
B Cell ◽  
Radioactive Iodine ◽  
Interleukin 2 ◽  
Dose Intensity ◽  
Response To Treatment ◽  
High Dose ◽  
Acth Stimulation ◽  
Antithyroid Antibodies ◽  
Cell Clones ◽  
Toxic Goiter

PURPOSE We investigated whether the association of interleukin-2 (IL-2) with hypothyroidism is related to the presence of thyroid autoantibodies, dose of IL-2, and clinical effectiveness of treatment, and reviewed the literature. PATIENTS AND METHODS Sixteen cancer patients were treated with high-dose recombinant, continuous infusion IL-2 (18 x 10(6) IU/m2/d) and lymphokine-activated killer (LAK) cells. One patient previously treated for a toxic goiter with radioactive iodine was analyzed separately. Thyroid function and levels of thyroid antibodies were determined regularly. RESULTS Seven of 15 patients (47%) became hypothyroid with high serum thyrotropin (TSH) levels within 60 to 120 days after the start of treatment; five responded favorably to treatment (one complete remission [CR], four partial remissions [PRs]), compared with none of the other eight patients. Two hypothyroid patients developed antimicrosomal antibodies (AMAs), one showed a further increase of antithyroglobulin antibodies (TgAbs), and six developed TgAbs. Only one of eight euthyroid patients developed slightly elevated TgAb levels. Development of hypothyroidism correlated significantly with a favorable response to treatment (r = .76, P = .001). The patient, treated with radioactive iodine, also became hypothyroid with high levels of TSH and development of AMAs and TgAbs. No difference was found between the hypothyroid and euthyroid patients in mean cumulative dose of IL-2 administered within the first 60 days or total treatment period, or with the relative dose-intensity. No other autoantibodies were found and patients had normal corticotropin (ACTH) stimulation tests. CONCLUSION The likelihood of developing (transient) hypothyroidism is higher in patients who respond to IL-2 treatment. The development of antithyroid antibodies suggests that IL-2 treatment triggers autoreactive B-cell clones or that cellular and/or cytokine-mediated thyroid destruction leads to activation of autoreactive B-cell clones.

scholarly journals Non-infectious cholecystopathy secondary to high-dose IL-2 cancer immunotherapy

2015 ◽  
Vol 4 (10) ◽  
pp. 205846011557945
Author(s):  
Kevin Kuppler ◽  
Daniel Jeong ◽  
Jung W Choi
Keyword(s):  
Cancer Immunotherapy ◽  
Specific Immunotherapy ◽  
Clinical Presentation ◽  
Correct Diagnosis ◽  
Interleukin 2 ◽  
Clinical History ◽  
High Dose ◽  
Imaging Data ◽  
Rare Manifestation ◽  
Cancer Immunotherapies

Interleukin-2 (IL-2) associated cholecystopathy is a rare manifestation of IL-2 drug toxicity in the setting of cancer immunotherapy. While the imaging data and clinical presentation can easily mimic acute cholecystitis, the correct diagnosis can be made with the particular clinical history, thus avoiding inappropriate surgical management. As more cancer immunotherapies become standard oncologic treatments, specific immunotherapy-associated side effects are also expected to be encountered more frequently in the future and should be recognized as such. We present a case of IL-2-associated cholecystopathy in the setting of renal cell carcinoma immunotherapy.

scholarly journals Long-term progression-free survival of patients with metastatic melanoma or renal cell carcinoma following high-dose interleukin-2

2021 ◽  
Vol 69 (4) ◽  
pp. 888-892
Author(s):  
Joseph I Clark ◽  
Brendan Curti ◽  
Elizabeth J Davis ◽  
Howard Kaufman ◽  
Asim Amin ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Melanoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Interleukin 2 ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival

High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC.

Should High-Dose Interleukin-2 Still be the Preferred Treatment for Patients with Metastatic Renal Cell Cancer?

2011 ◽  
Vol 26 (3) ◽  
pp. 273-277 ◽  
Author(s):  
Robert O. Dillman ◽  
Neil M. Barth ◽  
Louis A. VanderMolen ◽  
Warren H. Fong ◽  
Khosrow K. Mahdavi ◽  
...  
Keyword(s):  
Renal Cell Cancer ◽  
Renal Cell ◽  
Cell Cancer ◽  
Interleukin 2 ◽  
High Dose ◽  
Metastatic Renal Cell Cancer

Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3065-3072 ◽  
Author(s):  
Michael R. Verneris ◽  
Mobin Karami ◽  
Jeanette Baker ◽  
Anishka Jayaswal ◽  
Robert S. Negrin
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Malignant Cell ◽  
Leukemic Cells ◽  
Target Cells ◽  
High Dose ◽  
Effector Cells ◽  
Nkg2d Expression

Abstract Activating and expanding T cells using T-cell receptor (TCR) cross-linking antibodies and interleukin 2 (IL-2) results in potent cytotoxic effector cells capable of recognizing a broad range of malignant cell targets, including autologous leukemic cells. The mechanism of target cell recognition has previously been unknown. Recent studies show that ligation of NKG2D on natural killer (NK) cells directly induces cytotoxicity, whereas on T cells it costimulates TCR signaling. Here we demonstrate that NKG2D expression is up-regulated upon activation and expansion of human CD8+ T cells. Antibody blocking, redirected cytolysis, and small interfering RNA (siRNA) studies using purified CD8+ T cells demonstrate that cytotoxicity against malignant target cells occurs through NKG2D-mediated recognition and signaling and not through the TCR. Activated and expanded CD8+ T cells develop cytotoxicity after 10 to 14 days of culture, coincident with the expression of the adapter protein DAP10. T cells activated and expanded in low (30 U/mL) and high (300 U/mL) concentrations of IL-2 both up-regulated NKG2D expression equally, but only cells cultured in high-dose IL-2 expressed DAP10 and were cytotoxic. Collectively these results establish that NKG2D triggering accounts for the majority of major histocompatibility complex (MHC)–unrestricted cytotoxicity of activated and expanded CD8+ T cells, likely through DAP10-mediated signaling. (Blood. 2004;103: 3065-3072)

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