Antitumor efficiency of contact radiotherapy in combination with a chlorin-based photosensitizer in experiment

Authors have studied the antitumor efficacy of contact radiation therapy (CRT) in combination with a chlorin-based photosensitizer (PS) in an experiment on laboratory animals with transplanted tumors. The experimental study was performed in 50 white outbred rats weighing 250±50 g. Subcutaneously transplanted Pliss lymphosarcoma (PLS) and alveolar liver cancer RS1 (RS1) were used as tumor models. Chlorinbased PS photolon (RUE «Belmedpreparaty», Republic Belarus) was injected intravenously at a dose of 2.5 mg/kg. The radiation sessions were carried out 2.5–4 hours (depending on the tumor model) after the administration of the PS using the device «microSelectron HDR V3 Digital» («Nucletron», Netherlands) with a 192-Ir radiation source in single focal doses 5 and 10 Gy. All laboratory animals (for PLS and RS1) were subdivided into 5 groups of 5 animals each: intact control, CRT 5 Gy, CRT 10 Gy, PS + CRT 5 Gy, PS + CRT 10 Gy. For the PLS tumor model – on the 14th day from the beginning of the experiment Vav. in groups were 26.31±5.81; 22.45±6.97; 18.99±4.86; 10.75±5.18 and 28.06±2.85 cm3, respectively (p˂0.05). The coefficients of tumor growth inhibition in the experimental groups were 14.67%, 27.82%, 59.14% and 6.65%, respectively. The frequency of complete tumor regressions 60 days after the start of the experiment was 0%, 20%, 20%, 60%, and 20%, respectively. On RS1 tumor model – on the 14th day from the beginning of the experiment Vav. in groups were 4.48±1.03; 0.80±0.21; 0.29±0.09; 0.19±0.07 and 0.32±0.08 cm3, respectively (p=0.009). The coefficients of tumor growth inhibition in the experimental groups were 82.14%, 93.53%, 95.76% and 92.86%, respectively. The frequency of complete tumor regressions 60 days after the start of the experiment was 0%, 0%, 20%, 0%, and 0%, respectively. Systemic administration of chlorin-based PS before the CRT session increases the antitumor efficacy of radiation therapy in animals with transplantable tumors of different histological structure and growth patterns. The data obtained indicate that further studies of the radiosensitizing properties of PS are promising.

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Anti-Tumor Activity of the Aurora a Inhibitor MLN8237 in Diffuse Large B-Cell Lymphoma Preclinical Models.

Blood ◽

10.1182/blood.v112.11.1592.1592 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1592-1592 ◽

Cited By ~ 1

Author(s):

Jessica J Huck ◽

Mengkun Zhang ◽

Marc L Hyer ◽

Mark G Manfredi

Keyword(s):

Tumor Growth ◽

Growth Inhibition ◽

Tumor Model ◽

B Cell Lymphoma ◽

Tumor Growth Inhibition ◽

Aurora A ◽

Hct 116 ◽

Xenograft Models

Abstract Aurora A kinase is a serine/threonine protein kinase that is essential for normal transit of cells through mitosis. In many tumor types the Aurora A gene is amplified and/or the protein is over-expressed. The Aurora A small-molecule inhibitor MLN8237 demonstrated robust tumor growth inhibition in xenograft models of solid tumors grown subcutaneously (S.C.) in immunocompromised mice. Here we explored the antitumor activity of MLN8237 in models of diffuse large B-cell lymphoma (DLBCL) both in vitro and in vivo. In vivo three established DLBCL xenograft models (OCI-Ly7, OCI-Ly19, and WSU-DLCL2; all cells expressing luciferase) and a primary DLBCL tumor model PHTX-22-06 were tested using MLN8237 at different doses. Rituximab, an anti-CD20 monoclonal antibody that is active against CD20+ malignant B cells and is a standard of care agent was used for comparison. Using these model systems, tumor cells were injected either I.V. (to evaluate disseminated disease), or S.C. in severe combined immunodeficient mice (SCID). Animals were dosed orally for 21 days with MLN8237 (QD or BID) at various doses, or Rituximab dosed at 10mg/kg IV (once/week) and tumor growth inhibition was monitored using either bioluminescent imaging for the disseminated models or vernier calipers for the S.C. models. Tumor growth inhibition by MLN8237 was dose dependent with 20 mg/kg bid being the most efficacious dose (TGI>100% in both disseminated OCI-Ly19 and WSU models). All animals in the OCI-Ly19 disseminated model 20 mg/kg BID treatment group demonstrated regressions and remained disease free until the end of the study, day 65. In this study the Rituximab treated animals were euthanized on day 31 due to a high level of tumor burden. In the primary tumor model, PHTX-22-06, MLN8237 dosed at 20 mg/kg BID was also the most efficacious with a TGI of 95%. Moreover, tumor growth inhibition was durable as determined by prolonged tumor growth delay (>50 days). Significant efficacy was achieved in all models tested, whether grown as disseminated or subcutaneous models. A noted increase in durability of response was observed with MLN8237 treatment when compared with previous data from solid tumor models. In vitro, MLN8237 treatment increased levels of apoptosis in the OCI-Ly19 cells in comparison to the solid tumor cell line HCT-116 (colon). Greater Annexin V positive cells and greater cleaved PARP and Caspase-3 signals were detected in the MLN8237 treated OCI-Ly19 cells when compared to HCT-116 cells. The demonstration of robust and durable anti-tumor activity in preclinical models treated with MLN8237 provides the basis for its clinical evaluation as a treatment option for DLBCL. MLN8237 is currently in multiple Phase I clinical trials.

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Enhanced Activity of GA101, a Novel Type II, Glycoengineered CD20 Antibody, In Combination with Bendamustine or Fludarabine, and with the Bcl-2 Family Inhibitors ABT-737 or ABT-263

Blood ◽

10.1182/blood.v116.21.3915.3915 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3915-3915 ◽

Cited By ~ 1

Author(s):

Frank Herting ◽

Sabine Bader ◽

Pablo Umana ◽

Christian Klein

Keyword(s):

Tumor Growth ◽

Growth Inhibition ◽

Optimal Dose ◽

Tumor Growth Inhibition ◽

Superior Efficacy ◽

Combination Studies ◽

Equity Ownership ◽

Tumor Remission ◽

Complete Tumor

Abstract Abstract 3915 GA101 is type II, glycoengineered CD20 antibody currently in PhII/III clinical trials. GA101 mediates enhanced direct cell death with a concomitant reduction of CDC; and high ADCC induction due to increased affinity for FcgRIIIa. We have shown that GA101 compared to rituximab mediates superior efficacy in NHL xenograft models including the induction of complete tumor remission. In clinical practice the combination of rituximab with chemotherapy e.g. CHOP, CVP, bendamustine, fludarabine or FC results in a substantial clinical benefit. To assess the potential of GA101 for combination with bendamustine or fludarabine, in vivo combination studies in s.c. Z138 (MCL) xenografts in Scid beige mice were devised. GA101 and rituximab at sub-optimal doses of 1 mg/kg (once weekly) were combined with 3 mg/kg bendamustine (days 19, 20, 21, 22); or with 40 mg/kg fludarabine (days 22, 23, 24) and compared to the corresponding monotherapy arms. GA101 in combination with bendamustine mediated statistically superior efficacy in terms of tumor growth inhibition (TGI) compared to the combination of rituximab and bendamustine: TGI values on day 33 were 29% for rituximab, 42% for rituximab + bendamustine, 47% for GA101 and 72% for GA101 + bendamustine. Treatment with bendamustine did not show significant antitumor activity. Statistical evaluation based on sAUC showed a more than additive and significant effect on tumor growth for the combination of GA101 with bendamustine compared to the corresponding monotherapy arms. GA101 in combination with fludarabine demonstrated statistically superior efficacy in terms of TGI and yielded a significant difference compared to the combination of rituximab and fludarabine or GA101 as monotherpy. TGI values on day 36 were 50% for fludarabine, 60% for rituximab, 85% for rituximab + fludarabine, 86% for GA101 and >100% for GA101 + fludarabine. Furthermore, the superiority of the GA101-fludarabine combination was demonstrated by the observation of 3 tumor-free animals at the end of the study. ABT-263 (navitoclax) is a Bcl-2 family inhibitor that is currently in Phase I/II clinical trials for lymphoid malignancies. To provide evidence that GA101 can be combined with ABT-263 and the experimental Bcl-2 family inhibitor ABT-737, in vivo combination studies in s.c. SU-DHL4 (DLBCL) xenografts in Scid beige mice were devised. 10 mg/kg GA101 and rituximab (once weekly) were combined with 50 mg/kg ABT-737 (i.p., days 19, 22, 24, 26, 29, 31, 33). In a second study, 3 mg/kg GA101 or 10 mg/kg rituximab (once weekly) were combined with 100 mg/kg ABT-263 (orally, once daily). GA101 at a sub-optimal dose of 10 mg/kg demonstrated statistically superior efficacy in combination with ABT-737 in terms of tumor growth inhibition compared to GA101 alone or the combination of 10 mg/kg rituximab and ABT-737. Both combination treatments were statistically significant compared to the corresponding monotherapy arms. TGI values based on means on day 36 were 20% for ABT-737, 45% for rituximab, 92% for rituximab + ABT-737, 96% for GA101 and >100% for GA101 + ABT-737. The superiority of the combination of GA101 and ABT-737 was supported by complete tumor regression in all animals whereas none was observed with the combination of rituximab and ABT-737. GA101 at a sub-optimal dose of 3 mg/kg or rituximab at a dose of 10 mg/kg mediated statistically superior efficacy in terms of tumor growth inhibition in combination with ABT-263 compared to the respective monotherapy arms. TGI values based on means on day 43 were 15% for ABT-263, 89% for rituximab, >100% for rituximab + ABT-263, 80% for GA101 (at the sub-optimal dose) and >100% for GA101 (sub-optimal dose) + ABT-263. Taken together i) GA101 as single agent was at least as efficacious as the combination of rituximab with bendamustine, fludarabine or ABT-737; ii) the combination of GA101 with bendamustine or fludarabine was superior to the respective monotherapy arms and resulted in an enhanced, at least additive effect of the combination; iii) the combination of GA101 with Bcl-2 family inhibitors ABT-737 and ABT-263 was superior to the respective monotherapy arms and resulted in an enhanced effect of the combination including the induction of tumor remission. These data strongly support the further clinical investigation of GA101 in combination with Fludarabine, Bendamustine or Bcl-2 family inhibitors. Disclosures: Herting: Roche: Employment. Bader:Roche: Employment. Umana:Roche: Employment, Equity Ownership. Klein:Roche: Employment, Equity Ownership.

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848 Novel small molecule HPK1 inhibitor PCC-1 induces strong anti-tumor activity

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.848 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A889-A889

Author(s):

Sanjib Das ◽

Sravan Mandadi ◽

Jagmohan Saini ◽

Sachin Chaudhari ◽

Ameya Deshpande ◽

...

Keyword(s):

T Cell ◽

Tumor Growth ◽

Growth Inhibition ◽

Small Molecule ◽

Tumor Model ◽

Tumor Growth Inhibition ◽

Target Engagement ◽

Ct26 Tumor ◽

Syngeneic Model

BackgroundHematopoietic progenitor kinase 1 (HPK1, MAP4K1), is a negative regulator of T and B cell receptor signaling.1 2 3 A strong anti-tumor immunogenic response and tumor rejection was observed in mice with HPK1 gene knocked out.3 Treatment of HPK1 kinase dead mice with immune check-point blockers (ICBs) demonstrated enhanced tumor growth inhibition.3 Hence, HPK1 is an attractive therapeutic strategy for immuno-oncology based treatment in cancers. In comparison to our previous HPK1 small molecule inhibitor, PCC,4 we present here a differentiated novel HPK1 inhibitor, PCC-1 with good anti-T cell kinases selectivity and stronger anti-tumor efficacy in CT26 tumor model. In addition, using the syngeneic model of MC38 expressing human PD-L1, we present for the first time, the combination efficacy of a HPK1 inhibitor with the clinical ICB, Atezolizumab.MethodsIntuitive medicinal chemistry complemented by structure-based drug design was used to identify & develop potent inhibitors of HPK1 with optimal kinase selectivity, PK and in vivo efficacy profile. The SAR efforts were guided by biochemical assays, functional read-outs and primary human in vitro T-cell activation assays. In vivo target engagement and pharmacodynamic data was generated using CT26 and MC38-hPD-L1 tumor models.ResultsPCC-1 has sub-nanomolar HPK1 inhibition potency and strong target engagement resulting in pSLP76 inhibition, enhanced anti-tumor cytokine production of IL-2 and/or IFNgamma in Jurkat cells, human PBMCs and human whole blood. PCC-1 also demonstrated nanomolar potency in inducing a complete reversal of PGE2 or adenosine mediated immunosuppression. Oral dosing of PCC-1 as a single agent, induced strong tumor growth inhibition (TGI) in the syngeneic model of CT26 and MC38-hPD-L1 tumor models. Combination of PCC-1 with anti-CTLA4 in CT26 tumor model induced significantly greater TGI than anti-CTLA4 alone. Moreover, as a first, the combination of PCC-1 with clinical ICB, Atezolizumab in MC38-hPD-L1 induced enhanced rejection of tumors. These results strongly suggest PCC-1 as a promising candidate for HPK1 inhibition and as a combination partner with ICBs in clinic.ConclusionsPCC-1 is a novel, orally active HPK1 inhibitor that demonstrates excellent stand-alone efficacy and enhances current immunotherapy efficacy. Further evaluation of PCC-1 is ongoing to advance towards clinic.AcknowledgementsWe thank Dnyaneshwar Dahale, Sanjay Patale, Sandip Patil, Vidya Kattige, Jiju Mani, Namrata Singh, Ekta Kashyap, Sandeep Thorat, Pankaj Jain and Pramod Sagar for their contributions to the projectTrial RegistrationN/AReferencesKiefer F, et al. The EMBO Journal 1996.Hu, et al. Genes and Development 1996.Sawasdikosol, Burakoff. eLife 2020;9:e55122.Sachin S Chaudhari, et al. Poster#1709, AACR Annual Meeting April-May 2021.Ethics ApprovalThe studies involving animals have obtained ethics approval from Institutional Animal Ethics Committee (IAEC), The Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), New Delhi, India, GRC/IAEC/472/2020-1. Participants of the studies have given informed consent before taking part.

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