7 results on '"Ronald Slomba"'
Search Results
2. Abstract P4-06-07: Preliminary indications of safety and efficacy of neoadjuvant chemotherapy plus chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib) in triple negative breast cancer
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Shipra Gandhi, Mateusz Opyrchal, Cayla Ford, Ronald Slomba, Kristopher Attwood, Tracey O’Connor, Ellis Levine, and Pawel Kalinski
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Cancer Research ,Oncology - Abstract
BACKGROUND: Pathologic complete response (pCR) or microinvasive residual breast cancer (ypTmic) following neoadjuvant chemotherapy (NAC) is critical for good long-term outcomes in triple negative breast cancer (TNBC) patients (pts) but is achieved only in 40-50% of pts. Its combination with pembrolizumab, the new standard of care in TNBC, increases the pCR rate to 65% but is associated with significant immune-related and permanent toxicities. Higher intratumoral levels of CD8+ cytotoxic T-lymphocytes (CTLs) and low levels of regulatory T-cells (Treg) and myeloid derived suppressor cells (MDSC) predict improved relapse-free survival (RFS), overall survival (OS) and higher probability of pCR, a surrogate marker for RFS. Locally produced chemokines CCL5, CXCL9, CXCL10 and CXCL11 are critical for local infiltration with CTLs, while CCL22 is responsible for Treg attraction, with high CXCL9 expression being associated with a 3-fold higher rate of achieving pCR in response to NAC. Our preclinical data show that Chemokine-modulatory (CKM) regimen, combining rintatolimod (TLR3 agonist), interferon (IFN)-α2b and celecoxib (COX-2 inhibitor), selectively induces CTL-attractants but decreases MDSC- and Treg-attractants in the tumor microenvironment (TME). We hypothesized that the combination of CKM with paclitaxel will promote selective CTL infiltration into TNBC, and along with doxorubicin/cyclophosphamide (AC), will result in higher rate of pCR, translating into improved RFS and OS. METHODS: In the phase I study NCT04081389, 9 pts with stage I-III TNBC were enrolled with median age of 47 (37-55) years. All patients were treated with paclitaxel 80 mg/m2 IV weekly for 12 weeks, and for first 3 weeks days 1-3 also received CKM regimen consisting of rintatolimod 200 mg IV and celecoxib 200 mg oral twice daily. IFN-α2b was administered in an accelerated titration design at doses 0 or 5 million units (MU)/m2 [Dose Level (DL) 1,2 respectively] in first 2 pts (no intra-patient dose escalation), then 10 MU/m2 [DL 3] in 4 patients and then 20 MU/m2 [DL 4] in 3 patients. Pre- and 3 week-on treatment biopsies were performed at DL 3 and DL 4 (5 patients). This was followed by standard dose-dense AC and surgery. Dose-limiting toxicity (DLT) was defined as grade 3 or higher toxicity within the first 3 weeks of treatment. The primary endpoint was safety and tolerability, to determine the recommended phase II dose (RP2D) of CKM for extended efficacy study. The secondary endpoints included the efficacy (pCR), along with RFS and OS. Tumor and blood biomarkers were analyzed in exploratory studies. RESULTS: Treatment was well-tolerated with mostly grade 1 or 2 treatment-related adverse events (TRAEs) and no DLTs. Grade 3 TRAE were neutropenia (3/9), attributed to CKM (1/9) or paclitaxel (3/9), pneumonia (1/9) and anemia (1/9) attributed to AC. Two additional severe adverse events (pneumonia and squamous cell carcinoma of skin in situ) were observed, unrelated to study treatment. Paclitaxel- or AC-related toxicities were not higher than expected. There was no evidence of delayed or immune-related toxicities 90 days post-treatment. 5/9 (56%) pts attained pCR, and 1 additional pt had ypTmic at the time of surgery. There were no patients with progressive disease. All patients were able to get planned surgery with no additional delays observed. There was consistent (p=0.07) selective increase in CD8α (CTL marker) in on-treatment tumor biopsies with concomitant decrease in CD8α in the blood (p=0.04). CONCLUSIONS: The treatment was well-tolerated and no DLTs were observed and we determined RP2D for future studies. We observed promising clinical activity with pCR + ypTmic rate of 66%, comparable to pembrolizumab combination with NAC. A larger phase II study is being designed to confirm the observed efficacy and to determine if CKM regimen would be a safer short-term alternative to pembrolizumab or if CKM can overcome the resistance to the standard pembrolizumab/NAC therapy. Citation Format: Shipra Gandhi, Mateusz Opyrchal, Cayla Ford, Ronald Slomba, Kristopher Attwood, Tracey O’Connor, Ellis Levine, Pawel Kalinski. Preliminary indications of safety and efficacy of neoadjuvant chemotherapy plus chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib) in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-06-07.
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- 2023
3. 547 Safety and efficacy of de-escalated neoadjuvant chemoimmunotherapy of triple negative breast cancer (TNBC) using chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib)
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Shipra Gandhi, Mateusz Opyrchal, Cayla Ford, Ronald Slomba, Marie Quinn, Tracey O'Connor, Ellis Levine, and Pawel Kalinski
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- 2022
4. A randomized phase II trial of neoadjuvant chemokine modulation in patients with localized prostate cancer undergoing radical prostatectomy
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Karan Jatwani, Bailey Farmer, Arya Mariam Roy, Ronald Slomba, Kristopher Attwood, Ellis Glenn Levine, Eric Kauffman, Pawel Kalinski, Khurshid Guru, Dharmesh Gopalakrishnan, and Gurkamal S. Chatta
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Cancer Research ,Oncology - Abstract
TPS406 Background: Most patients with high or very high risk localized prostate cancer (PCa) experience disease recurrence after radical prostatectomy (RP). Neoadjuvant androgen ablation has not improved high-risk pathological features or recurrence rates after RP.1 We reported the association between high intratumoral CD8+ T lymphocyte (CTL) density and improved survival post-RP, suggesting clinical benefit from neoadjuvant immunomodulation (NI).2 Analysis of the tumor immune microenvironment after NI may also provide key insights into potential therapeutic strategies in PCa. CTL/NK/Th1-recruiting chemokines (CCL5, CXCL9 and CXCL10) are downregulated while MDSC/Treg-attracting chemokines (CCL2, CCL22, and CXCL12) are upregulated in human PCa tissue.3 A large proportion of T cells in PCa are Tregs or dysfunctional CTLs and this immunosuppressive profile may be partly driven by COX-2 upregulation.4,5 A chemokine modulating regimen (CKM) of rintatolimod (TLR-3 ligand), aspirin (COX-2 inhibitor), and IFN-α favorably reprogrammed the chemokine profile and CTL/Treg ratio in human PCa explants.3 This combination has demonstrated safety in phase I/II trials across other tumor types, though it is unclear if IFN-α can be omitted without compromising efficacy.7-8 Methods: This is a three-arm, phase II trial where patients with localized PCa scheduled to undergo RP are randomized in 1:1:1 ratio to a 2-week regimen of neoadjuvant CKM triplet (rintatolimod + aspirin + IFN-α) vs CKM doublet (rintatolimod + aspirin) vs no CKM. Thirty patients will be enrolled to assess CD8+ T cell density in the RP specimen as the primary endpoint. Pathological and PSA responses, surgical margin positivity, and safety/toxicity of the CKM combinations will be secondary endpoints. Pre- and post-treatment density of various infiltrating T cell subtypes, MDSCs, chemokine and chemokine receptor profiles, immune checkpoint expression, immune-regulatory gene expression signatures, and peripheral blood immune cell landscape will be key exploratory endpoints. The trial is currently open with 11 patients enrolled. Clinical trial ID: NCT03899987 . References: 1) Scolieri MJ, J Urol 2000, 2) Clin Oncol 36, 2018: suppl; abstr 5068, 3) Muthuswamy R, Prostate 2016, 4) Sfanos KS, Prostate 2009, 5) Gupta S, Prostate 2000, 6) NCT01545141, 7) NCT02151448, 8) NCT02432378.
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- 2023
5. Abstract CT145: Systemic rintatolimod and interferon-α2b selectively reprogram local tumor microenvironment in patients with metastatic triple negative breast cancer for enhanced influx of cytotoxic T-lymphocytes but not regulatory T-cells
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Shipra Gandhi, Mateusz Opyrchal, Melissa Grimm, Ronald Slomba, Kathleen Kokolus, Sebastiano Battaglia, Kristopher Attwood, Adrienne Groman, Lauren Williams, Mary Lynne Tarquini, Paul Wallace, Kah Teong Soh, Tracey O'Connor, Amy Early, Ellis Levine, Igor Puzanov, Marc Ernstoff, and Pawel Kalinski
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Cancer Research ,Oncology - Abstract
Background: Effective immune therapies depend on the presence of cytotoxic T-lymphocytes (CTLs) in the tumor microenvironment (TME). Our preclinical data showed synergy between TLR3 ligands and interferon-α (IFN-α) in reprogramming the TME, but not healthy tissues, to selectively enhance CTL attraction, providing rationale for their systemic application to enhance local CTL densities in “cold” tumors. The pilot study NCT03599453 evaluated the safety of systemic chemokine modulating regimen (CKM) composed of i.v. rintatolimod (Ampligen; selective TLR3 ligand) and IFN-α, and its ability to promote local CTL influx to mTNBC lesions. Methods: Six evaluable patients (33-75 years) with mTNBC received 6 doses of rintatolimod (200 mg i.v.), IFN-α (INTRON-A; 20MU/m2 i.v.) and COX-2 inhibitor (celecoxib; 2 x 200 mg, p.o.) over 2 weeks, with tumor biopsies obtained before (within 6 days) and after (within 5 days) CKM. All patients received follow-up pembrolizumab (200 mg, i.v, Q3 weeks). The primary endpoint was the change in the CTL marker CD8α in the TME with a planned interim analysis after 3 patients (α=0.03) and final analysis after 6 patients (α=0.084). Correlative studies analyzed additional markers of CTLs, regulatory T-cells (Tregs), and CTL- and Treg-attracting chemokines in the TME and blood. Results: Treatment was well tolerated with mostly grade 1/2 adverse events and one grade 3 clinically significant pneumonitis and immune thrombocytopenic purpura observed during follow up pembrolizumab treatment. We observed uniform increases of intratumoral type-1 immune markers upon treatment: CD8α mRNA (6.1-fold; p=0.034), GZMB (3.5-fold; p=0.058), ratios of CD8α/FOXP3 and GZMB/FOXP3 (5.7-fold; p=0.036, and 7.6-fold; p=0.024 respectively), and CTL attractants CXCL10 (2.6-fold; p=0.104) and CCL5 (3.3-fold; p=0.019), successfully meeting the primary endpoint. In contrast, neither Treg marker Foxp3 nor Treg attractants CCL22 or CXCL12 were enhanced. These TME changes were accompanied by transient decreases in circulating CD3+CD8+ CTLs and CD3-CD56+ NK cells (but not Tregs), selectively affecting the cells expressing CXCR3 (receptor for CXCL10), but not CCR4 or CXCR4 (receptors for CCL22 and CXCL12). Three patients had stable disease lasting 2.4, 2.5 and 3.8 months, as of September 1, 2021 cut-off. An additional patient had a partial response (breast auto-amputation) with massive tumor necrosis observed in the post-CKM biopsy. Conclusion: This proof-of-concept study shows that short-term systemic CKM followed by pembrolizumab is safe and selectively enhances local CTL infiltration in the TME, providing rationale for concurrent CKM and PD1 blockade in prospective phase II studies. Citation Format: Shipra Gandhi, Mateusz Opyrchal, Melissa Grimm, Ronald Slomba, Kathleen Kokolus, Sebastiano Battaglia, Kristopher Attwood, Adrienne Groman, Lauren Williams, Mary Lynne Tarquini, Paul Wallace, Kah Teong Soh, Tracey O'Connor, Amy Early, Ellis Levine, Igor Puzanov, Marc Ernstoff, Pawel Kalinski. Systemic rintatolimod and interferon-α2b selectively reprogram local tumor microenvironment in patients with metastatic triple negative breast cancer for enhanced influx of cytotoxic T-lymphocytes but not regulatory T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT145.
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- 2022
6. Abstract 3127: Negative impact of paclitaxel on human breast tumor microenvironment and its reversal by the combination of interferon-α with TLR3 agonist rintatolimod
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Shipra Gandhi, Melissa Grimm, Ronald Slomba, Kazuaki Takabe, and Pawel Kalinski
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Cancer Research ,Oncology - Abstract
Background: Taxanes are extensively used in the chemotherapy of breast cancer in the neoadjuvant, adjuvant and metastatic settings. Paclitaxel is known to have both immunostimulatory and immunosuppressive effects, but its impact on the chemokine system within the tumor microenvironment (TME) remains unclear. In the breast TME treated with neoadjuvant taxane chemotherapy, high levels of the cytotoxic T cell (CTL) attractants CXCL9, CXCL10 and their common receptor CXCR3 predict higher probability of pathological complete response (pCR) and improved long term outcomes. We previously developed a chemokine modulatory regimen (CKM) combining interferon-α with TLR3 agonist rintatolimod to selectively increase CTL-attracting chemokines in the TME but reduce the production of chemokines attracting myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) in the TME. Here we evaluated paclitaxel’s impact on chemokine production in the human breast TME and CKM’s ability to eliminate undesirable aspects of taxane chemotherapy. Methods: Fresh breast cancer tissues obtained during routine surgeries, breast cancer cell lines BT-549 and MDA-MD-231 and peripheral blood monocyte-derived macrophages were analyzed immediately or cultured ex vivo for 24 hours in the absence or presence of paclitaxel and/or CKM components. The expression of chemokine genes and secretion of chemokines by freshly harvested and ex vivo-treated tumor explants, cancer cell lines and macrophages were analyzed by quantitative PCR (Taqman) and ELISA. Paired student t-test was used for statistical analyses. Results: Breast cancer explants spontaneously expressed high levels of MDSC/Treg-attractants CXCL12 and CCL22, but only marginal levels of CTL and natural killer (NK) cell attractants CXCL9, CXCL10, CXCL11 and CCL5. Unexpectedly, paclitaxel treatment resulted in further elevation of granulocyte/MDSC-attractant CXCL8 and CCL22, which was reversed by the combination of paclitaxel with CKM. At the same time, while paclitaxel alone did not induce any of the CTL attractants tested, its combination with the CKM was highly effective in inducing CXCL9, CXCL10, CXCL11 and CCL5. Conclusions: Our results identify an undesirable aspect of paclitaxel’s impact on breast cancer. The ability of CKM to enhance the expression of CTL/NK cell attractants and suppress the production of Treg/MDSC attractants produced by paclitaxel provides a strong rationale for combined use of CKM in taxane-based chemo-immunotherapy of breast cancer and potentially other diseases. Citation Format: Shipra Gandhi, Melissa Grimm, Ronald Slomba, Kazuaki Takabe, Pawel Kalinski. Negative impact of paclitaxel on human breast tumor microenvironment and its reversal by the combination of interferon-α with TLR3 agonist rintatolimod [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3127.
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- 2022
7. Abstract CT105: Initial results of a phase II study evaluating a chemokine-modulatory (CKM) regimen in patients with colorectal cancer metastatic to the liver
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Sarbajit Mukherjee, Patrick M. Boland, Melissa Grimm, Ronald Slomba, Kristopher Attwood, Renuka Iyer, and Pawel Kalinski
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Cancer Research ,Oncology - Abstract
Background: Liver metastases develop in 20-50% of colorectal cancer (CRC) patients, being typically resistant to immune checkpoint inhibitors (ICIs) and having a poor prognosis. Our preliminary data showed synergy between IFNα and TLR3 ligands in selectively enhancing the intratumoral production of CD8+ T cell (CTL) attracting chemokines (but not Treg attractants) in ex vivo-treated CRC explants and preferential impact of this combination on liver-metastatic CRC tumor tissues (rather than surrounding liver tissues). Based on these data and previous reports showing the prognostic value of intratumoral CTLs in the CRC outcomes, we hypothesized that systemic infusion of the combination of IFNα2b with rintatolimod (selective TLR3 ligand for i.v. use) can reprogram local balance between the CTL- and regulatory T cell (Treg)-attracting chemokines and the resulting patterns of immune infiltrate in liver lesions. Methods: Recurrent/metastatic CRC patients with unresectable liver metastases amenable to biopsy were eligible. Patients had prior treatment (Rx) with fluoropyrimidine, irinotecan, oxaliplatin, and an anti-EGFR targeted therapy (if RAS wt), or contra-indication to such. Patients received IFNα2b IV (20 million units/m2 IV daily) and rintatolimod (200 mg IV daily) plus oral celecoxib (200 mg twice daily) on days 1, 2, 3, 8, 9, 10, 15, 16, and 17. Response assessment was done via liver biopsies (pre-Rx and on day 24 ± 4 days) and CT imaging (RECIST v1.1) on D46. The primary endpoint was the change in CD8+ T-cells before Rx, with that seen post-Rx (measured by quantitative RT-PCR as a ratio of CD8α to a housekeeping gene, HPRT). With a sample size of N=12 evaluable pts, the study design had a 90% power to detect a 0.77 standard deviation increase (pre- to post Rx) at a significance level of 0.1 (ClinicalTrials.gov Identifier: NCT03403634). Results: Nineteen patients with microsatellite stable (MSS) CRC were enrolled between Apr 2018 and Oct 2020, 15 were treated and 12 were evaluable for the primary endpoint. Most were male (75%, N=9) and Caucasian (92%, N=11). The median age at diagnosis was 65 years. Most had previously received three or more prior lines of therapy (58%, N=7). The study's primary endpoint was met, evidenced by increased CD8a expression post-treatment (p=0.046). An increase in ratios of CD8a/CD4 (p=0.03), CD8a/FOXP3 (p Conclusion: Our study demonstrated that a combinatorial CKM regimen could re-program the immunosuppressive tumor microenvironment in MSS CRC patients with liver metastasis, raising the possibility that the CKM regimen can be used to enhance the effectiveness of ICIs in this group of patients. Citation Format: Sarbajit Mukherjee, Patrick M. Boland, Melissa Grimm, Ronald Slomba, Kristopher Attwood, Renuka Iyer, Pawel Kalinski. Initial results of a phase II study evaluating a chemokine-modulatory (CKM) regimen in patients with colorectal cancer metastatic to the liver [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT105.
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- 2022
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