P1/2, N=169, Recruiting, Sanofi | N=126 --> 169 | Trial completion date: Nov 2026 --> Oct 2030

P1/2, N=18, Recruiting, Sanofi

In vivo, CYT-303 showed no toxicity or cytokine release in cynomolgus monkeys up to the highest dose (60 mg/kg), administered weekly by intravenous infusion for 28 days. These results demonstrate the potential of CYT-303 to be a safe and effective therapy against HCC.

CYT-303 efficacious doses identified in the HCC model together with safety in cynomolgus monkeys and planned human pharmacokinetic modeling studies support clinical evaluation of CYT-303 in first in human HCC clinical trials.

This work demonstrates that KI of IL-15 and KO of TGFβR2 is a promising strategy for TALEN®-engineered iNK cell therapies to overcome the immunosuppressive TME and mount a potent and persistent anti-tumor immune response. The data also provide a solid foundation for combining these edited iNK cells with CYT-303 to address the immunosuppressive TME towards a cure for HCC.

CYT-338 mediates potent anti- tumor activity against MM cell lines and patient tumors in the presence of effector cells (PBNK, iNK or MM patient NK cells). Evidence for additional CYT-338 effector function invoking macrophages and complement mediated MM tumor killing was obtained. Differential gene expression analysis provides mechanistic clues for a distinct cytotoxicity profile for CYT-338 from daratumumab that supports further evaluation of this potent anti-CD38 antibody.

In vitro results revealed that P. pavonica and J. rubens extracts caused significant decreases in the number and viability of Hep-G2 cells in a dose-dependent manner as compared to untreated Hep-G2 cells or Cisplatin-treated Hep-G2 cells...Flow cytometric analysis showed that P. pavonica and J. rubens extracts at the treatment and the prophylactic doses resulted in a significant increase in the phenotypic expressions of CD4 T, CD8 T, and CD335 cells compared to naïve EAC mouse. Overall, both extracts P. pavonica and J. rubens possess potential antitumor and antitumor immunological effects with less toxicity, opening new approaches for further studies of the chemical and biological mechanisms behind these effects.

Conclusions Pharmacologically active CYT-303 doses were identified. CYT-303 can help recruit NK cells to the tumor site to achieve tumor growth inhibition.

E2 and PRL, either alone or in combination, decreased soluble MICA secretion in all CC cell lines, while E2 solely increased soluble MICA secretion in SiHa cells. On the whole, the present study provides evidence that E2 and PRL mediate the mechanisms through which NK and CC cells mediate a cytotoxic response and these have an antagonistic effect on NK cell-mediated cytotoxicity.

Density of NK cells infiltrating in lung metastases was increased after combination treatment. Metformin effectively enhances local and abscopal effects of RT though the activation of cell-mediated immunity and might be clinically useful for LARC.

Additional analysis revealed that significant amounts of IL-2 could be produced by tumor-derived CD4 and CD8CD45RA memory T-cells after combined anti-CD3/anti-CD28 stimulation. Our data indicate that both blockade of inhibitory KIR and IL-2 triggering of tumor-derived NK-cells are necessary to enhance NK-cell responsiveness in GBM.

Local RT (4Gy x 2) suppressed the growth of s.c tumor to approximately half of control group although not statistically significantly (p=0.067). Metformin alone did not significantly suppress the tumor growth. However, when combined with RT, tumor weight at day28 was markedly reduced as compared with control group (p<0.01).

Next, we used a syngeneic mouse model of LLC (Lewis lung cancer) vs cisplatin resistant LLC-CR, to examine the effects of AT-0174 (170 mg/kg; P.O. once daily) in combination with anti-PD1 antibody (10 mg/ml; I.P. once every 3 days)...Treatment with AT-0174 resulted in higher tumor infiltrating lymphocytes of Teffs and NK and lower Treg frequency in LLC-CR tumors than treatment with a selective IDO1 inhibitor (epacadostat)...Support by the Dept. of Veterans Affairs.

CYT-303 greatly enhanced the cytotoxic activity of iNKs and cytolysis of Hep3B tumor cells in-vitro. CYT-303 and iNK cells, alone or in combination, demonstrate anti-tumor activity against HCC that warrants clinical development.

Lenalidomide: 25mg p.o. on days 1-21/cycle or thalidomide: 100 mg p.o. on days 1-28; in pts ≥75 years of age 50mg p.o. on days 1-28, dexamethasone: 40 mg p.o. on days 1, 8, 15, 22 (± 1 day), in pts ≥ 75 years of age 20 mg p.o. this treatment was administered for nine cycles. Furthermore, higher numbers of specific NK subsets such as those with a circulatory phenotype, correlated with better outcome. These results highlight the prognostic potential of immune monitoring and the interconnection between specific subsets of the immune environment with the course of the disease.

The CD335 (natural killer cells) were increased in the CRC-induced mice and limonin treatment restored them to normal levels suggesting reinstatement to normal colon conditions. Limonin apparently mitigated CRC development, by ameliorating adaptive immune responses (CD8, CD4, and CD19), reducing inflammation (serum prostaglandin E2; TNF-α, innate immune responses) and oxidative stress, and enhancing the endogenous anti-oxidation defense reactions (GSH) in CRC-induced mice.