29 research outputs found
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CD68+ tumor-associated myeloid cells as the target of adenosine-induced gene products and predictor of response to adenosine blockade with ciforadenant (cifo) in renal cell cancer (RCC)
5025 Background: Adenosine in the tumor microenvironment (TME) is immunosuppressive and may play a role in resistance to immunotherapy. We described an adenosine induced gene expression signature (AS, Fong, Cancer Disc 2020) that correlates with response to therapy with cifo, an adenosine A2A receptor antagonist, as monotherapy or in combination with atezolizumab in refractory RCC. These genes express chemokines that signal through CCR2 and CXCR2 to recruit myeloid cells including immunosuppressive tumor associated-M2 macrophages, which are thought to mediate resistance to anti-PD(L)1 treatment. We now identify tumor infiltrating CD68+ myeloid cells as the effector cell for adenosine mediated immunosuppression. Methods: 82 RCC pts have been treated in an ongoing Phase 1/1b trial evaluating cifo (100mg po bid) monotherapy or combination with atezolizumab (840mg IV q 2 weeks). Tumor biopsies, obtained at screening and on therapy, are available for analysis in 32 pts to date. RNA expression was measured in tumors using Nanostring. Immunohistochemistry (IHC) for CD68 was performed on biopsies with CD68+ tumors defined as > 4% tumor area containing CD68+ cells. Results: Pt characteristics are median age 63; median prior therapies 3, with 72% failing prior anti-PD(L)1. Gene expression of M2 markers consisting of CD68 (p = 0.0008) and CD163 (p = 0.03) was higher in baseline samples from AS+ compared to AS- pts. By IHC, 10 pts had CD68+ cells infiltrating the tumor; 9 of 10 AS+. Tumor regression was observed in 6 of 10 CD68+ pts (N = 3 monotherapy and 3 combination) including 4 partial responses (PR, RECIST). No PRs and 2 minor responses were seen in 22 pts who were CD68- (p < 0.005). Median time to progression was not reached for CD68+ vs 2 mo for CD68-. Paired biopsies showed a significant reduction in infiltrating CD68+ cells (p = 0.03) with treatment including 2 of 2 evaluable PRs. Conclusions: Adenosine immunosuppression is mediated by M2 macrophages, which can be reversed by cifo. Enumerating tumor infiltrating CD68+ cells may be a valuable biomarker for identifying pts that will respond to adenosine blockade. Clinical trial information: NCT02655822
Outcomes of anti-PD-1 therapy in mesothelioma and correlation with PD-L1 expression
This abstract is freely available on the conference website at (see link below
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Adenosine receptor blockade with ciforadenant +/- atezolizumab in advanced metastatic castration-resistant prostate cancer (mCRPC)
129 Background: Adenosine, generated by the ectonucleotidase CD73, mediates immunosuppression within the tumor microenvironment by triggering adenosine 2A receptors (A2AR) on immune cells. Tumor CD73 expression may be prognostic in prostate cancer. We evaluated the clinical activity of adenosine blockade using A2AR antagonist, ciforadenant, with or without the anti-PDL-1 antibody, atezolizumab (atezo), in advanced mCRPC patients (pts) in an ongoing phase 1 trial. Methods: Eligibility required measurable disease and up to 5 prior systemic therapies. Prior anti- PD-(L)1 was allowed. Ciforadenant was administered orally BID as monotherapy at 50-200mg or 100mg in combination with atezo 840mg IV Q 2 weeks (wks). Safety and efficacy were evaluated by CTCAE4, RECIST1.1 and PCWG2. Serum was obtained for measurement of cytokines. Results: Of 33 enrolled pts, 10 received ciforadenant monotherapy and 23 in combination with atezo. As of 10/21/19, 14 pts are evaluable for response and described further. Median prior therapies is 3 (range 2-6) with median follow-up 10.8 (4-33) wks. Metastatic burden included 4 node only, 2 bone plus node, and 8 visceral metastases. Five pts experienced tumor regression: 2 ciforadenant monotherapy (tumor reductions 12%, 17%); and 3 combination (tumor reductions 4%, 27%, 42%). The pt with a partial response had PSA decline from 98 ng/mL to <1. Eight pts had stable disease (SD) for a clinical benefit rate (SD + PR) of 8/14 (57%). Median duration of disease control was 24 wks. Study treatment was well tolerated with two Gr3/4 adverse events (AEs) of fatigue (1) and anorexia (1). The most common Gr1/2 AEs were fatigue and nausea. Serum TNFα levels increased by 4-8 wks on therapy in 12/13 pts. Baseline levels of soluble VCAM-1, which has been implicated in metastatic spread/more aggressive disease, were higher in pts with tumor regression (771 ± 109 ng/mL, n=4) than pts with tumor growth (544 ± 62 ng/mL, n=5, p<0.05). Conclusions: Results from this phase 1 study show mCRPC can be sensitive to A2AR blockade with ciforadenant. Cytokine changes provide evidence of treatment-induced inflammatory response, which may predict efficacy. Data on all 33 enrolled pts will be presented. Clinical trial information: NCT02655822