A Retrospective, Observational Analysis of Tumor Infiltrating Lymphocytes and Tumor Regression in Melanoma

Purpose Adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, can mediate objective tumor regression in a majority of patients with metastatic melanoma (52 of 93; 56%). Addition and intensification of total body irradiation (TBI) to the preparative lymphodepleting chemotherapy regimen in sequential trials improved objective partial and complete response (CR) rates. Here, we evaluated the importance of adding TBI to the adoptive transfer of tumor-infiltrating lymphocytes (TIL) in a randomized fashion. Patients and Methods A total of 101 patients with metastatic melanoma, including 76 patients with M1c disease, were randomly assigned to receive nonmyeloablative chemotherapy with or without 1,200 cGy TBI before transfer of tumor-infiltrating lymphcytes. Primary end points were CR rate (as defined by Response Evaluation Criteria in Solid Tumors v1.0) and overall survival (OS). Clinical and laboratory data were analyzed for correlates of response. Results CR rates were 24% in both groups (12 of 50 v 12 of 51), and OS was also similar (median OS, 38.2 v 36.6 months; hazard ratio, 1.11; 95% CI, 0.65 to 1.91; P = .71). Thrombotic microangiopathy was an adverse event unique to the TBI arm and occurred in 13 of 48 treated patients. With a median potential follow-up of 40.9 months, only one of 24 patients who achieved a CR recurred. Conclusion Adoptive cell transfer can mediate durable complete regressions in 24% of patients with metastatic melanoma, with median survival > 3 years. Results were similar using chemotherapy preparative regimens with or without addition of TBI.

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Influence of Gender on Radiosensitivity during Radiochemotherapy of Advanced Rectal Cancer

Cancers ◽

10.3390/cancers14010148 ◽

2021 ◽

Vol 14 (1) ◽

pp. 148

Author(s):

Barbara Schuster ◽

Markus Hecht ◽

Manfred Schmidt ◽

Marlen Haderlein ◽

Tina Jost ◽

...

Keyword(s):

Quality Of Life ◽

Rectal Cancer ◽

Body Weight ◽

Chromosomal Aberrations ◽

Tumor Regression ◽

Tumor Infiltrating Lymphocytes ◽

Advanced Rectal Cancer ◽

The Body ◽

Infiltrating Lymphocytes

Gender is increasingly recognized as an important factor in medicine, although it has long been neglected in medical research in many areas. We have studied the influence of gender in advanced rectal cancer with a special focus on radiosensitivity. For this purpose, we studied a cohort of 495 men (84.1% ≥ T3, 63.6% N1, 17.6%, M1) and 215 women (84.2% ≥ T3, 56.7% N1, 22.8%, M1) who all suffered from advanced rectal cancer and were treated with radiochemotherapy. The energy deposited, DNA double-strand break (dsb) repair, occurrence of chromosomal aberrations, duration of therapy, tumor regression and tumor-infiltrating lymphocytes, laboratory parameters, quality of life and survival were assessed. The residual DNA dsb damage 24 h after irradiation in lymphocytes was identical in both sexes. Furthermore, chromosomal aberrations accurately reflecting radiosensitivity, were similar in both sexes. There were no gender-dependent differences in tumor regression, tumor-infiltrating lymphocytes and outcome indicating no differences in the radiosensitivity of cancer cells. The irradiated tumor volume in women was slightly lower than in men, related to body weight, no difference was observed. However, when the total energy deposited was calculated and related to the body weight, women were exposed to higher amounts of ionizing radiation. During radiochemotherapy, decreases in blood lymphocyte counts and albumin and several quality-of-life parameters such as nausea and vomiting, loss of appetite, and diarrhea were significantly worse in women. There is no difference in radiation sensitivity between men and women in both normal tissue and tumors. During radiochemotherapy, the quality of life deteriorates more in women than in men. However, women also recover quickly and there are no long-term differences in quality of life.

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Immunotherapy in liver tumors: II. Intratumoral injection with activated tumor-infiltrating lymphocytes, intrasplenic administration of recombinant interleukin-2 and interferon α causes tumor regression and lysis

Cancer Letters ◽

10.1016/0304-3835(94)90236-4 ◽

1994 ◽

Vol 85 (1) ◽

pp. 39-46 ◽

Cited By ~ 9

Author(s):

David L. Liu ◽

Carl H. Håkansson ◽

J. Seifert

Keyword(s):

Liver Tumors ◽

Tumor Regression ◽

Interleukin 2 ◽

Tumor Infiltrating Lymphocytes ◽

Intratumoral Injection ◽

Interferon Α ◽

Recombinant Interleukin 2 ◽

Infiltrating Lymphocytes

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Density and distribution of lymphocytes in pretherapeutic rectal cancer and response to neoadjuvant therapy

Gastroenterology Report ◽

10.1093/gastro/goaa016 ◽

2020 ◽

Author(s):

Sicong Lai ◽

Xiaoying Lou ◽

Xinjuan Fan ◽

Weipeng Sun ◽

Yanhong Deng ◽

...

Keyword(s):

Rectal Cancer ◽

Neoadjuvant Therapy ◽

Tumor Regression ◽

Tumor Infiltrating Lymphocytes ◽

Sensitivity Analyses ◽

Tumor Regression Grade ◽

Cancer Tissue ◽

Infiltrating Lymphocytes ◽

Regression Grade

Abstract Background Lymphocytic density in rectal cancer has been reported to be associated with therapeutic response, but the role of the lymphocytic distribution pattern remains to be determined. This study aimed to evaluate the association between the distribution and density of lymphocytes in rectal-cancer tissue with tumor response to neoadjuvant therapy. Methods We retrospectively analysed 134 patients with rectal cancer receiving neoadjuvant therapy within a prospectively maintained cohort. Pretherapeutic biopsy samples were stained with immunohistochemistry (CD4 and CD8). Densities of intratumoral periglandular lymphocytes (IPLs) and tumor-infiltrating lymphocytes (TILs) were assessed separately. Logistic-regression analysis was used to assess associations of lymphocyte densities with tumor regression grade (TRG), controlling for clinicopathological, molecular, and regimen features. Results Compared with cases in the lowest quartile of CD8+ TILs, those in the highest quartile were significantly associated with better TRG (multivariate odds ratio, 0.23; 95% confidence interval, 0.07 to 0.76; P < 0.001). In contrast, CD8+ IPLs, CD4+ IPLs, and CD4+ TILs were not significantly associated with TRG (P = 0.033, 0.156, and 0.170, respectively). Sensitivity analyses detected no interaction between CD8+ TILs and regimen of neoadjuvant radiation (Pinteraction = 0.831) or chemotherapy (Pinteraction = 0.879) on TRG. Conclusions Our data suggest that CD8+ TILs, but not IPLs, are independently associated with response to neoadjuvant therapy, regardless of the regimen of radiation or chemotherapy.

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Tumor-Infiltrating Lymphocytes in Biopsy Specimens Obtained 7 Days after Starting Chemoradiotherapy for Rectal Cancer Are Predictors of the Response to Chemoradiotherapy

Oncology ◽

10.1159/000508922 ◽

2020 ◽

Vol 98 (12) ◽

pp. 869-875

Author(s):

Hiroshi Miyakita ◽

Sotaro Sadahiro ◽

Toshiyuki Suzuki ◽

Lin Fung Chan ◽

Takashi Ogimi ◽

...

Keyword(s):

Rectal Cancer ◽

Immunohistochemical Staining ◽

Tumor Regression ◽

Tumor Infiltrating Lymphocytes ◽

High Density ◽

Shrinkage Rate ◽

Tumor Shrinkage ◽

Cd4 Cells ◽

Biopsy Specimens ◽

Infiltrating Lymphocytes

Background: Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision surgery is a standard treatment for locally advanced rectal cancer (LARC). Tumor-infiltrating lymphocytes (TILs) have been reported to be associated with tumor response; however, this remains to be established. We previously reported that histological changes on biopsy specimens obtained 7 days after starting nCRT are strong predictors of response to nCRT. Methods: The subjects were 208 patients with LARC who received nCRT. TILs on hematoxylin-eosin staining together with immunohistochemical staining of lymphocyte surface markers including CD3, CD4, CD8, and FoxP3 were performed both on the biopsy specimens before and 7 days after starting nCRT. Results: The proportions of patients with high densities of CD3+, CD4+, CD8+, and FoxP3+ cells 7 days after starting CRT were significantly lower than the respective values before starting nCRT (p < 0.0001, p < 0.0001, p = 0.0023, and p = 0.0046). In biopsy specimens obtained before treatment, high-density CD4+ cells and FOXP3+ cells were significantly associated with tumor shrinkage rate. High-density FOXP3+ cells were significantly associated with marked tumor regression. In biopsy specimens obtained 7 days after starting treatment, high-density CD4+ cells were significantly associated with marked tumor regression, tumor regression grade 1, and tumor shrinkage rate. High-density FoxP3+ cells were significantly associated with marked tumor regression and tumor shrinkage rate. Conclusions: In patients who received nCRT for LARC, the evaluations of immunohistochemical staining for CD4+ and FOXP3+ TILs were more intimately related to histological response to CRT and tumor shrinkage rates in biopsy specimens obtained 7 days after starting treatment than in biopsy specimens obtained before CRT.

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Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2025570118 ◽

2021 ◽

Vol 118 (30) ◽

pp. e2025570118

Author(s):

Shamin Li ◽

Yannick Simoni ◽

Summer Zhuang ◽

Austin Gabel ◽

Shaokang Ma ◽

...

Keyword(s):

T Cells ◽

Immune Checkpoint ◽

Tumor Regression ◽

Tumor Model ◽

Tumor Infiltrating Lymphocytes ◽

Immune Checkpoint Blockade ◽

T Cell Response ◽

Histocompatibility Complex ◽

Infiltrating Lymphocytes

Neoantigen-specific T cells are strongly implicated as being critical for effective immune checkpoint blockade treatment (ICB) (e.g., anti–PD-1 and anti–CTLA-4) and are being targeted for vaccination-based therapies. However, ICB treatments show uneven responses between patients, and neoantigen vaccination efficiency has yet to be established. Here, we characterize neoantigen-specific CD8+ T cells in a tumor that is resistant to ICB and neoantigen vaccination. Leveraging the use of mass cytometry combined with multiplex major histocompatibility complex (MHC) class I tetramer staining, we screened and identified tumor neoantigen–specific CD8+ T cells in the Lewis Lung carcinoma (LLC) tumor model (mRiok1). We observed an expansion of mRiok1-specific CD8+ tumor-infiltrating lymphocytes (TILs) after ICB targeting PD-1 or CTLA-4 with no sign of tumor regression. The expanded neoantigen-specific CD8+ TILs remained phenotypically and functionally exhausted but displayed cytotoxic characteristics. When combining both ICB treatments, mRiok1-specific CD8+ TILs showed a stem-like phenotype and a higher capacity to produce cytokines, but tumors did not show signs of regression. Furthermore, combining both ICB treatments with neoantigen vaccination did not induce tumor regression either despite neoantigen-specific CD8+ TIL expansion. Overall, this work provides a model for studying neoantigens in an immunotherapy nonresponder model. We showed that a robust neoantigen-specific T-cell response in the LLC tumor model could fail in tumor response to ICB, which will have important implications in designing future immunotherapeutic strategies.

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ACT Up TIL Now: The Evolution of Tumor-Infiltrating Lymphocytes in Adoptive Cell Therapy for the Treatment of Solid Tumors

Immuno ◽

10.3390/immuno1030012 ◽

2021 ◽

Vol 1 (3) ◽

pp. 194-211

Author(s):

Thomas Morgan Hulen ◽

Christopher Aled Chamberlain ◽

Inge Marie Svane ◽

Özcan Met

Keyword(s):

Tumor Regression ◽

Adoptive Cell Therapy ◽

Treatment Options ◽

Tumor Infiltrating Lymphocytes ◽

Adoptive Cell Transfer ◽

Autologous Tumor ◽

Cancer Type ◽

Act Up ◽

Cancer Immunotherapies ◽

Infiltrating Lymphocytes

The past decades of cancer immunotherapy research have provided profound evidence that the immune system is capable of inducing durable tumor regression. Although many commercialized anti-cancer immunotherapies are available to patients, these treatment options only scrape the surface of the potential immune-related treatment possibilities for cancer. Additionally, many individuals are ineligible for established immunotherapies due to their cancer type. The adoptive cell transfer of autologous tumor-infiltrating lymphocytes has been used in humans for over 30 years to treat metastatic melanoma, and continued modifications are making it increasingly more effective against other types of cancer. This comprehensive review outlines this therapy from its infancy through to the present day, bringing to light modifications and optimizations to the traditional workflow, as well as highlighting the influence of new methods and technologies.

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