Background

CC-90010, a potent oral BETi, was well-tolerated with promising activity in pts with advanced malignancies. We present longer follow-up results of parts A (A) and B (B) from CC-90010-ST-001 and, for the first time, results from part C (C) describing food effect on CC-90010 pharmacokinetics (PK).

Methods

CC-90010-ST-001 is a phase I dose-escalation (A) and -expansion (B) study of CC-90010 in pts with aSTs and R/R DLBCL also evaluating high-calorie/-fat meal effects on CC-90010 PK in pts with aSTs (C); 11 dose levels (DLs) and 4 schedules (2 weekly [2 d on/5 d off; 3 d on/4 d off], 1 biweekly [3 d on/11 d off] and 1 monthly [4 d on/24 d off]) were tested. Primary objectives were safety, tolerability, maximum tolerated dose and recommended phase II dose (RP2D). Secondary and exploratory objectives were antitumor activity, PK, pharmacodynamics and food effect.

Results

As of 3 Nov 2020, 133 pts were enrolled. In A and B, 67 and 2 pts had aSTs; 2 and 21 pts had R/R DLBCL. In C, 41 pts had aSTs. In A, 6 pts (11%) had dose-limiting toxicities across dosing schedules. The most common grade 3/4 treatment-related adverse event (TRAE) was thrombocytopenia (A, 16%; B, 76%; C, 10%); 8 pts (12%) in A, 6 (29%) in B, and 2 (5%) in C had serious TRAEs. In A, 1 pt (progressing grade 2 astrocytoma) had a complete response (CR) before progression (19 cycles); 1 pt (endometrial carcinoma) had a partial response (PR; 8 cycles). In B, 2 pts with R/R DLBCL responded (CR, PR). In C, 2 pts (parotid basal cell adenocarcinoma, nasopharyngeal cancer) had durable PRs, and 23 had stable disease (≥4 mo in 9 pts); 1 pt (relapsing glioblastoma) had a minor response. Plasma exposures rose dose-proportionally across DLs. CC-90010 terminal half-life was ∼60 h and PK was similar under fasted vs fed conditions in C. CC-90010 ≥25 mg caused ≥50% decrease in CCR1 mRNA (BETi blood biomarker) 4 h after last dose. CCR1 modulation was similar in A and B after first and last dose at the RP2D.

Conclusions

Overall, CC-90010 was very well tolerated with promising antitumor activity and PK not impacted by food intake, supporting exploration in combination therapy.

Clinical trial identification

NCT03220347; EUDRACT 2015-004371-79.

Editorial acknowledgement

Writing and editorial assistance were provided by Brittany L. Phillips, PhD, of Bio Connections LLC, funded by Bristol Myers Squibb Company.

Legal entity responsible for the study

Celgene, a Bristol-Myers Squibb Company.

Funding

Celgene, a Bristol-Myers Squibb Company.

Disclosure

V. Moreno: Advisory/Consultancy: BMS; Advisory/Consultancy: Bayer; Advisory/Consultancy: Pieris; Advisory/Consultancy: Janssen. M. Vieito Villar: Advisory/Consultancy: Debio; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: TFS; Travel/Accommodation/Expenses: Merck-Serono. J.M. Sepulveda Sanchez: Speaker Bureau/Expert testimony: Astellas; Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy, Travel/Accommodation/Expenses: AbbVie; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Celgene, a Bristol-Myers Squibb Company; Advisory/Consultancy: GW Pharma. O. Saavedra: Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Kyowakirin. C. Carlo Stella: Honoraria (self), Speaker Bureau/Expert testimony: MDS; Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self): BMS; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): ADCT; Advisory/Consultancy: Sanofi; Research grant/Funding (institution): Novartis; Travel/Accommodation/Expenses: Takeda; Honoraria (self), Travel/Accommodation/Expenses: Janssen. J-M. Michot: Honoraria (self): Celgene; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): AstraZeneca; Honoraria (self): Janssen. A. Italiano: Advisory/Consultancy, Research grant/Funding (self): Bayer; Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy: Springworks; Advisory/Consultancy: Epizyme; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Merck; Research grant/Funding (self): MSD; Research grant/Funding (self): PharmaMar. M. Magagnoli: Honoraria (self): Sanofi; Honoraria (self): AstraZeneca. C. Carpio: Advisory/Consultancy: Regeneron; Advisory/Consultancy, Travel/Accommodation/Expenses: Takeda; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Gilead; Travel/Accommodation/Expenses: Sandoz; Travel/Accommodation/Expenses: Celgene. R. Sarmiento: Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, a Bristol-Myers Squibb Company. B. Amoroso: Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene. I. Aronchik: Shareholder/Stockholder/Stock options, Full/Part-time employment: BMS. E. Filvaroff: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: BMS; Shareholder/Stockholder/Stock options: Amgen; Shareholder/Stockholder/Stock options: Gilead; Shareholder/Stockholder/Stock options: Genentech/Roche. B. Hanna: Research grant/Funding (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: BMS. A. Pinto: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self): Celgene; Honoraria (self): Servier; Honoraria (self): BMS; Honoraria (self): MSD; Advisory/Consultancy: Novartis; Travel/Accommodation/Expenses: Takeda. Z. Nikolova: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, a Bristol-Myers Squibb Company. I. Braña: Research grant/Funding (self): Celgene, a Bristol-Myers Squibb Company. All other authors have declared no conflicts of interest.

Background

Natural compounds are recently booming as promising immunomodulatory anticancer agents in several cancers including breast cancer (BC). Recently, our group has shown the anticancer activity of several phytoconstiuents through repressing several oncogenic signals. Yet, unraveling their regulatory effect at the immune synapse is still a virgin field. The immune suppressive tumor microenvironment (TME) represents the rate limiting step in the success of any immunotherapeutic approach. Thus our aim is to identify a natural compound to trim the immune suppressive TME through its regulatory effect on a recent class of complex regulators known as competing endogenous RNAs. Ursolic acid (UA) is a phytoconstituent that is abundant in rosemary. Its anticancer activity has been confirmed. Yet, the molecular mechanisms behind it is still unraveled. In this study, we intended to investigate the anti-cancer and immunological effects of UA on BC through the regulation of a pool of ceRNAs and immune suppressive cytokines at the TME of BC cells.

Methods

Computational target prediction analysis was performed. UA was isolated from rosemary. MDA-MB-231 cells were treated with different concentrations of UA (20-100μM). IC50 value was calculated using dose response curve. MTT, colony forming assay and Scratch assay were performed. Total RNA was extracted and quantified by qRT-PCR. IL-10 anf TNF-α Elisa Kits were used.

Results

In-silico, miR-17-5p, MALAT-1 and H19 were found to target the immune suppressive cytokines IL-10 and TNF-α with high binding scores. UA resulted in a dose- and time-dependent repression of several BC hallmarks such as cellular viability, clonogenicity and migration capacity. Molecularly, UA was found to alter the ceRNAs network through inducing miR-17-5p and MALAT1 levels in treated cells compared to vehicle control BC cells. Yet, H19 was found to be repressed. At the Immune synapse, UA was found to repress IL-10 and TNF-α mRNA and protein levels.

Conclusions

This study crystallizes a novel mechanism of Rosemary and UA as promising immunoregulatory anticancer agents at the BC immune synapse through altering H19/MALAT-1/miR-17-5p circuit and the immune suppressive cytokines: IL-10 and TNF-α.

Legal entity responsible for the study

German University in Cairo.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Over the past decades, accumulating research evidences revealed that abnormal expressions of long non-coding RNAs (lncRNAs) are associated with tumour initiation, progression, metastasis, and resistance to cancer therapies. Therefore, lncRNAs are considered to be potential biomarkers for many cancer types. In the current study, we examined the expression and molecular mechanisms of a newly identified lncRNA called RNA associated with metastasis 11 (RAMS11) and its association with the development of colorectal cancer (CRC).

Methods

Quantitative RT-PCR was used to determine the expression of RAMS11 in 4 CRC cell lines (DLD-1, HT-29, HCT-116, and SW480) and normal colon cells CCD-112-CoN. To evaluate the biological and physiological functions of RAMS11 in CRC cells, CCK-8 cell proliferation assay, colony formation assay, and wound healing migration assay were performed after RAMS11 knockdown. The expressions of autophagy/apoptosis/mTOR/EMT pathway proteins were determined by Western blotting to evaluate the molecular mechanisms of RAMS11 in CRC cells.

Results

We found that RAMS11 was significantly upregulated in CRC cell lines compared to the normal cells. The knockdown of RAMS11 reduced CRC cells proliferation, and migration through mTOR dependent induction of autophagy, promotion of apoptosis, and inhibition of epithelial-mesenchymal transition (EMT) process.

Conclusions

Overall, our results suggested that RAMS11 is an important oncogenic regulator of CRC initiation and progression whereas, targeting RAMS11 and the related molecular pathways could be used as potential therapeutic strategies for CRC management.

Legal entity responsible for the study

The authors.

Funding

This project is partially supported by: (1) Research grant to HKL including Departmental Seeding Fund and Internal Institutional Research Fund (P0031318-UAHS); (2) Postgraduate studentship from The Hong Kong Polytechnic University for ZIK.

Disclosure

All authors have declared no conflicts of interest.

Background

Immune check-point inhibitors (ICPi) are routinely used in cancer treatment in the United Kingdom and are associated with immune-related adverse events (irAE). Most patients with autoimmune disease (AID) are often excluded from clinical trials investigating ICPi, due to hypothetical increased risks of AID flare or severe irAE, but these risks have never been conclusively verified. We present experience using ICPi at a UK tertiary cancer centre, comparing the irAE profile and efficacy in patients with pre-existing AID to those without.

Methods

This was a single centre retrospective analysis of electronic records of solid tumour patients who received treatment with an ICPi from January 2017 to December 2020. From a total of 562 patients, 15 had pre-existing AID. These were compared to those without AID in a 1:3 matched cohort for tumour-type and treatment.

Results

The AID cohort had inflammatory bowel disease (N=5), psoriasis (N=3), rheumatoid arthritis (N=2), polymyalgia rheumatica (N=2), autoimmune endocrinopathies (N=4), lupus (N=1) and sarcoidosis (N=1). 3 patients had 2 co-existing AID. All 15 patients had well controlled AID. 9 were on hormone replacement, immunosuppressive (prednisolone <10mg, n=2, mesalazine, n=1), or topical agents. 6 were not on AID treatment. The table below lists patient demographics, irAE and outcomes. 3 out of 15 AID patients had irAE possibly linked to their underlying AID (1 psoriasis, 1 RA, 1 colitis; no G3 or higher). No significant differences were found in the number of G3 or higher irAE, treatment discontinuation due to irAE, response to treatment, or survival between cohorts. Table: 31P

Patient demographics, irAE and outcomes

Conclusions

Exacerbation of pre-existing AID was infrequent and did not result in severe toxicity. Patients with well-controlled AID could be considered for entry in clinical trials involving ICPi.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype. At present, TNBC patients do not have an approved targeted therapy. Therefore, patients primarily depend on systemic chemotherapy that has inevitable detrimental side effects and show inadequate therapeutic outcomes leading to a high mortality rate. Hence, there is an urgent need to develop targeted therapies for the TNBC population. Emphasizing new nanotherapeutics approaches to combinational therapy could be an effective alternative tactic.

Methods

We designed a self-assembly strategy to design a highly biocompatible organic polyaniline (PANi) smart polymer nanotherapeutic (NPs) doped hyaluronan (HA) converting the PANi emeralidine base (EB) to emeralidine salt (ES) for strong near infrared (NIR)-mediated photothermal cancer treatment (PTCT). Therefore, smartly designed NPs at 808 nm exhibited a high extinction coefficient 8.23 x 108 M^-1 cm^-1, and adequate photothermal conversion efficiency (PCE) (η=41.6 %) made it an efficient photothermal agent (PTA), highly beneficial for selective CD44-mediated photothermal ablation of TNBC tumors. Furthermore, we have co-encapsulated imiquimod (R837-Toll-like receptor 7 agonist) immunoadjuvant molecules (HA-PANi/R837 NPs) to trigger a strong immune response against post-PTCT tumor.

Results

Encouragingly, targeted HA-PANi/R837 NPs selectively destroyed the tumor under NIR-illumination then released tumor-associated antigens. PTCT also triggered R837 release for the unprecedented role NPs-based immune therapy producing immunological cell death (ICD) of residual tumor cells, efficiently protecting the mice from tumor relapse and metastasis.

Conclusions

The specific high-performance of tumor-targeting homotypic ablation in targeted TNBC models was achieved without noticeable adverse effects on normal cells. Therefore, our smart biocompatible potential nanoplatform could serve as a photothermal immunotherapy modality for future utilization of chemotherapeutics-free clinical treatment. Thus, photothermally activated ICD has the greatest potential of dual-modal cancer therapy, preventing future relapse by the activation of the immune system to recognize and kill the tumor cells.

Legal entity responsible for the study

The author.

Funding

Department of Biotechnology, Government of India.

Disclosure

The author has declared no conflicts of interest.