Anti-GARP: Combatting Treg Cells and TGF-β in the Tumor Microenvironment

AbbVie has recently licensed rights to a monoclonal antibody discovered by Argenx, ARGX-115, paying $20MM up-front and up to $625MM in milestones based on development, approval, and commercial performance. This monoclonal antibody targets a central player in the complex tumor microenvironment – the regulatory T-cell (Treg). Continue reading

Turning “cold tumors hot” – rationale, major setback, and promise

One of the most active fields of clinical investigation in immuno-oncology today is augmenting responses to checkpoint [CTLA4 or PD-(L)1] inhibition therapy by re-sensitizing tumors that were initially unresponsive or had stopped responding to treatment. Continue reading

Mutational burden biomarker – not just mismatch repair deficiency

We have discussed mutational burden previously on this blog – in essence, the concept is that tumors with more mutations are more visible to the immune system because the generation of new novel antigenic epitopes allows for adaptive immune responses even when previous adaptive antigen-specific immune responses have been blunted by PD-1 expression. Continue reading

Adenosine – a critical checkpoint in the tumor microenvironment

The tumor microenvironment (TME) includes a host of cells (mesenchymal, immune, vascular), cytokines, and other signaling molecules that serve to abrogate the innate and adaptive immune responses against the tumor. This is appropriate to maintain tissue homeostasis, and to prevent autoimmunity after the rogue cancer cells have been eliminated. Cancer cells co-opt many of these pathways to terminate the effective immune response so that they are not wiped out, rather, proliferate, invade, metastasize and kill, Continue reading

SEMA4D/CD100, a novel target for immune-oncology

Semaphorins are secreted, transmembrane, and glycosylphosphatidylinisotol-anchored glycoproteins that are important in cell to cell signaling. Humans have 20 semaphorins, the most of any species analyzed to date. Their role was originally identified in the development of the nervous system and axonal guidance. Since then, they have been shown to be important in the development and functioning of many tissues including: Continue reading

Decoy double strand breaks lead to mitotic catastrophe independent of BRCA1/2 mutations status

BRCA1/2 are DNA repair enzymes that are the essential components of homologous repair (HR), which is invoked when DNA doubles strand breaks are encountered. HR works via consultation of sister chromatids during late S to early G2 of the cell cycle – without repair of double strand breaks, mitotic catastrophe ensues: Continue reading

Ubiquitin specific protease 7 – a good target for cancer therapy

Ubiquitin specific protease 7 (USP7) is a deubiquitinase, an enzyme that removes ubiquitin a 76 amino acid protein that is added onto lysines in the target protein. Proteins that are mono, or poly (up to 10 residues), ubiquitinated are taken to the proteasome for destruction. Continue reading

Daratumumab effective in front-line multiple myeloma

Anti-CD38 monoclonal antibody daratumumab (Darzalex) is indicated for the treatment or patients with multiple myeloma that have failed prior treatment. CD38 is a Continue reading

How important is inflammation in breast cancer progression?

Not very, according to the REACT Study conducted by the Imperial College London. The study was predicated on the importance of COX-2 in driving inflammation that contributes to tumorigenesis. The thinking was that administering celecoxib (Celebrex), a COX-2 inhibitor, could reduce breast cancer progression, as suggested in smaller observational trials. Continue reading

CAR T-cell more effective than standard of care in refractory Non-Hodgkin Lymphoma

The FDA granted approval of axicabtagene ciloleucel (YESCARTA) on October 25, 2017, two months following the approval of tisagenlecleucel (KYMRIAH) – both are anti-CD19-directed CAR T (chimeric antigen receptor T-cell) therapies that employ re-programmed autologous T-cells to fight cancer: Continue reading