The combination therapy with EpCAM/CD3 BsAb and MUC-1/CD3 BsAb elicited antitumor immunity by T-cell adoptive immunotherapy in lung cancer

BackgroundHigh-dose radiotherapy (RT) is known to be immunogenic, but is rarely capable of driving clinically relevant abscopal antitumor immunity as monotherapy. RT is known to increase antigen presentation, type I/II interferon responses, and immune cell trafficking to irradiated tumors. Bempegaldesleukin (NKTR-214) is a CD122-preferential interleukin 2 (IL-2) pathway agonist that has been shown to increase tumor-infiltrating lymphocytes, T cell clonality, and increase PD-1 expression. NKTR-214 has increased drug half-life, decreased toxicity, and increased CD8+T cell and natural killer cell stimulation compared with IL-2.MethodsAnimals bearing bilateral subcutaneous MCA-205 fibrosarcoma or CT26 colorectal tumors were treated with NKTR-214, RT, or combination therapy, and tumor growth of irradiated and abscopal lesions was assessed. Focal RT was delivered using a small animal radiation research platform. Peripheral and tumor-infiltrating immune phenotype and functional analyses were performed by flow cytometry. RNA expression profiling from both irradiated and abscopal lesions was performed using microarray.ResultsWe demonstrate synergy between RT of a single tumor and NKTR-214 systemic therapy resulting in dramatically increased cure rates of mice bearing bilateral tumors compared with RT or NKTR-214 therapy alone. Combination therapy resulted in increased magnitude and effector function of tumor-specific CD8+T cell responses and increased trafficking of these T cells to both irradiated and distant, unirradiated, tumors.ConclusionsGiven the increasing role of hypofractionated and stereotactic body RT as standard of care treatments in the management of locally advanced and metastatic cancer, these data have important implications for future clinical trial development. The combination of RT and NKTR-214 therapy potently stimulates systemic antitumor immunity and should be evaluated for the treatment of patients with locally advanced and metastatic solid tumors.

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Effects of trilaciclib prior to chemotherapy ± atezolizumab on T-cell activation in patients with newly diagnosed extensive-stage small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20582 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20582-e20582

Author(s):

Aaron D. Stevens ◽

Davey B. Daniel ◽

Jerome H. Goldschmidt ◽

Paul A. Fields ◽

Barb Banbury ◽

...

Keyword(s):

Lung Cancer ◽

T Cell ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Antitumor Immunity ◽

Clonal Expansion ◽

Small Cell ◽

Small Cell Lung ◽

Antitumor Response ◽

Extensive Stage

e20582 Background: Chemotherapy ± immunotherapy has demonstrated meaningful clinical benefit to patients (pts) with extensive-stage small cell lung cancer (ES-SCLC); however, chemotherapy-induced damage to the immune system can potentially diminish treatment efficacy. Trilaciclib (T) is an intravenous cyclin-dependent kinase 4/6 inhibitor that protects hematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection) and may directly enhance antitumor immunity. Here, we evaluated the immune effects of T in pts with ES-SCLC receiving T or placebo (P) prior to first-line etoposide plus carboplatin (E/C) or E/C plus atezolizumab (E/C/A) in two phase 2 clinical trials. Methods: Genomic DNA, extracted from peripheral blood mononuclear cells (baseline and on treatment) and archival tumor tissue (baseline), was analyzed using the immunoSEQ® Assay (Adaptive Biotechnologies). T-cell receptor (TCR) β CDR3 regions were amplified and sequenced to identify and quantitate the abundance of each unique TCRβ CDR3. Clonal frequencies were compared at baseline and on treatment, and statistical differences between T and P were determined by Wilcoxon rank sum test. Antitumor response was defined as complete/partial response. Results: In both studies, peripheral T-cell clonal expansion was greater among pts receiving T versus P. Among pts receiving E/C, those in the T/E/C group with an antitumor response had significantly more peripheral clonal expansion than P responders (median 23 vs 12 clones; P= 0.04) and a greater number of tumor-associated expanded clones ( P= 0.03). T responders had more newly detected expanded peripheral clones compared with P responders (6 vs 1.5 clones; P= 0.06) and T nonresponders ( P= 0.02). Increased clonal expansion in T responders was more evident after two cycles of E/C versus four, suggesting that T results in a rapid T-cell response. Similarly, among pts receiving E/C/A, those in the T/E/C/A group with an antitumor response had significantly more peripheral clonal expansion than P responders (median 90 vs 43 clones; P= 0.002) and T nonresponders ( P= 0.016). T responders also had more newly expanded peripheral clones compared with P responders (68 vs 11 clones; P= 0.003) and T nonresponders ( P= 0.02). There was no increase in tumor-associated expanded clones among T responders compared to P responders, possibly due to the time point at which clonal expansion was assessed (after four cycles) or the addition of atezolizumab. Associations between peripheral and tumor-associated clonal expansion and survival will be presented. Conclusions: The data suggest that, among pts treated with T/E/C or T/E/C/A, increased clonal expansion is associated with clinical response, indicating that T may enhance antitumor immunity in pts with ES-SCLC treated with chemotherapy.

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Abstract A125: Pulsatile MEK inhibition improves antitumor immunity and T-cell function in Kras mutant lung cancer

10.1158/2326-6074.cricimteatiaacr18-a125 ◽

2019 ◽

Author(s):

Hyejin Choi ◽

Jiehui Deng ◽

Shuai Li ◽

Tarik Silk ◽

Elliott J. Brea ◽

...

Keyword(s):

Lung Cancer ◽

T Cell ◽

Antitumor Immunity ◽

Cell Function ◽

Mek Inhibition ◽

T Cell Function

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OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis

Journal of Experimental Medicine ◽

10.1084/jem.20082205 ◽

2009 ◽

Vol 206 (5) ◽

pp. 1103-1116 ◽

Cited By ~ 144

Author(s):

Daniel Hirschhorn-Cymerman ◽

Gabrielle A. Rizzuto ◽

Taha Merghoub ◽

Adam D. Cohen ◽

Francesca Avogadri ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Combination Therapy ◽

Antitumor Immunity ◽

Effector T Cells ◽

T Cell Response ◽

Therapeutic Interventions ◽

T Cell Apoptosis ◽

Combined Use ◽

Cellular Target

Expansion and recruitment of CD4+ Foxp3+ regulatory T (T reg) cells are mechanisms used by growing tumors to evade immune elimination. In addition to expansion of effector T cells, successful therapeutic interventions may require reduction of T reg cells within the tumor microenvironment. We report that the combined use of the alkylating agent cyclophosphamide (CTX) and an agonist antibody targeting the co-stimulatory receptor OX40 (OX86) provides potent antitumor immunity capable of regressing established, poorly immunogenic B16 melanoma tumors. CTX administration resulted in tumor antigen release, which after OX86 treatment significantly enhanced the antitumor T cell response. We demonstrated that T reg cells are an important cellular target of the combination therapy. Paradoxically, the combination therapy led to an expansion of T reg cells in the periphery. In the tumor, however, the combination therapy induced a profound T reg cell depletion that was accompanied by an influx of effector CD8+ T cells leading to a favorable T effector/T reg cell ratio. Closer examination revealed that diminished intratumoral T reg cell levels resulted from hyperactivation and T reg cell–specific apoptosis. Thus, we propose that CTX and OX40 engagement represents a novel and rational chemoimmunotherapy.

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