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:

cardiovascular, endocrine, gastrointestinal, hepatic, immune, musculoskeletal, renal, reproductive, and respiratory systems. A common theme in the mechanisms of semaphorin function is that they alter the cytoskeleton and the organization of actin filaments and the microtubule network. These effects occur primarily through binding of semaphorins to their receptors, although transmembrane semaphorins also serve as receptors themselves.

Where are SEMA4D receptors expressed, and what do they mediate?

SEMA4D is also known as CD100 because it is expressed on T-cells. It binds to CD72, which is expressed on B-cells, dendritic cells, macrophages, and mast cells. The high affinity receptor for SEM4D is also expressed on epithelial cells and endothelial cells (inducing angiogenesis and endothelial cell migration), and low-affinity receptors are present on damaged keratinocytes.

Figure 1. Multiple functions mediated by Sema 4D/CD100-plexin B counter-receptors. (a) As a ligand, the ligation of Sema 4D/CD100 with the low-affinity receptor CD72 stimulates the activation of, proliferation of and antibody production by B cells, promotes the maturation of and antigen presentation by dendritic cells (DCs), and induces the production of cytokines (IL-12, TNF-α, IL-6 and IL-8) by monocytes (Mo). (b) The binding of Sema 4D/CD100 molecules, which can be in both membrane-bound form (expressed on T cells or tumor cells) and soluble form (sCD100) (shed from activated T cells or tumor cells), to the high-affinity receptor plexin B1, which is expressed on endothelial and epithelial cells, induces angiogenesis and endothelial cell migration. (c) Damaged keratinocytes produce a self-antigen, plexin B2, and cocksackie adenovirus receptor (CAR), which can be recognized by the γδ T-cell receptor (TCR), Sema 4D/CD100, and the junctional adhesion molecule-like molecule (JAML), respectively, of dendritic epidermal γδ T cells (DETCs). These morphologically rounded DETCs release keratinocyte growth factor type 1 (KGF1) and KGF2, which may induce the proliferation and migration of keratinocytes and the restoration of epithelial integrity. https://www.nature.com/articles/cmi201265

Why is SEMA4D a good target for immuno-oncology?

SEMA4D is broadly expressed in many cancers and correlates with invasiveness. It is found at the leading edge of invasive cancers and functions to block T-cells from penetrating into the tumor microenvironment. Antibodies to SEMA4D have been shown to permit penetration of tumors by T-cells, reduce Tregs, induce the release of TNFα and IFNg, and induce a pro-inflammatory (as opposed to immune-suppressive) environment. Given these effects, combination therapy with checkpoint inhibitors, chemotherapy, angiogenesis inhibitors, and radiation is rational.

Figure 2. Effects of VX15/2503 MAb against SEMA4D. http://www.vaccinex.com/wp/wp-content/uploads/2014/12/vx15moalrg.jpg

Vaccinex is developing VX15, an IgG4 monoclonal antibody that binds to SEMA4D – two Phase 1 trials in patients with advanced solid tumors have been conducted. Across all dose levels, 17 of 42 patients exhibited stable disease for at least 8 weeks; nine patients have shown stable disease for at least 16 weeks.

A Phase 1b/2 study of VX15/2503 combined with avelumab (Bavencio, anti-PDL1) in patients with non-small cell lung cancer (NSCLC) is currently underway:

This is a phase 1b/2 study, designed to evaluate the safety, tolerability, and efficacy of VX15/2503 in combination with avelumab in immunotherapy-naïve subjects diagnosed with advanced (stage IIIB/IV) NSCLC who have either progressed on cytotoxic chemotherapy or declined first-line treatment with cytotoxic chemotherapy. The primary objective (Dose Escalation Phase) is to evaluate the safety and tolerability of ascending doses of VX15/2503 Q2W in combination with avelumab 10mg/kg Q2W. The second primary objective (Dose Expansion Phase) is to evaluate safety and tolerability of the recommended phase 2 dose of VX15/2503 administered in combination with 10 mg/kg avelumab Q2W. The secondary objectives include (Dose Expansion Phase), a preliminary estimate of efficacy using the following in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, Objective Response (OR), Duration of Response (DoR) and Progression-Free Survival (PFS), as well as making a preliminary estimate of efficacy using the following in accordance with iRECIST, OR, DoR and PFS. Additional secondary objectives are to characterize the pharmacokinetics profile of VX15/2503 and avelumab administered Q2W in combination, evaluate the immunogenicity of VX15/2503 and avelumab administered Q2W and evaluate VX15/2503 and avelumab pharmacodynamics markers including but not limited to receptor occupancy. Exploratory objectives include identification of candidate biomarkers of activity and biomarkers that may predict response to treatment with combination therapy of VX15/2503 and avelumab.

Enrollment will involve approximately 40 individuals who are 18 years of age or older with advanced non-small cell lung cancer. The study will be divided into two phases, dose escalation with up to 18 patients and dose expansion with up to 28 subjects. Subjects that are enrolled in the dose escalation phase may continue into the dose expansion phase, as long as there is no evidence of disease progression. The subjects entering the dose expansion phase from dose escalation, may have their dose increased to the recommend phase 2 dose, once it is determined. Any subjects that have evidence of disease progression will be taken off of treatment and will have a post treatment safety follow-up visit 10 weeks after last treatment. Subjects that have discontinued study drug will also continue to be followed every 3 months for survival, or lost to follow-up. It is estimated that the study will take approximately 33 months between first subject enrolled and last subject visit.

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

transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab.

We have reviewed its mechanism of action in depth, previously.

In a Phase 3 trial of 569 patients with multiple myeloma who had received at least one prior therapy, patients receiving daratumumab plus lenalidomide and dexamethasone (DRd) had a 63% reduction in risk of disease progression or death versus patients receiving lenalidomide and dexamethasone, alone (Rd). The PFS (progression-free survival) for patients receiving daratumumab had not been reached, while the PFS for patients not receiving daratumumab was 18.4 months – [HR] = 0.37; 95% CI 0.27 to 0.52, p < 0.0001 – representing a 63% reduction in risk of disease progression or death.

Figure 1. Kaplan Meier plot of patients receiving daratumumab, lenalidomide, and dexamethasone (DRd) versus lenalidomide and dexamethasone, alone (Rd).
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761036s004lbl.pdf

Daratumumab in front-line multiple myeloma

Given the impressive results in second-line, investigators sought to evaluate daratumumab in front-line therapy for multiple myeloma. Front-line treatment includes bortezomib, a proteasome inhibitor that is especially effective in multiple myeloma – it acts by blocking the proteasomal degradation of misfolded proteins and IkB, which inhibits NFkB. In addition to inducing apoptosis by blocking the turnover of misfolded antibody proteins by the proteasome, bortezomib is effective in myeloma cells, due to the specific effects of NFkB – (1) it controls genes for VEGF and adhesion molecules; (2) induces the secretion of autocrine growth factors IL-4 and IL-6.

In a Phase 3 study conducted in Europe and Latin America (n =  350) in patients with newly diagnosed multiple myeloma who were not candidates for bone marrow transplant, the addition of daratumumab to standard therapy of bortezomib (Velcade), melphalan, prednisone (VPM) was evaluated. Patients receiving VPM had a median progression-free survival of 18.1 months, while the median PFS had not been reached in patients receiving daratumumab-VPM with 27 months of follow-up (p < 0.0001). At 18 months of follow-up, 72% of daratumumab-VPM patients were alive without disease progression. Ninety-one percent of daratumumab-VPM patients had an objective response, versus 72% for VPM patients. Similarly, just 6% of VPM patients achieved minimal residual disease versus 22% of daratumumab-VPM patients (p < 0.0001).

These results are consistent with data seen in a second-line Phase 3 study (n = 498 patients) in which daratumumab (DVd) was added to bortezomib and predisone (Vd) –  the median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39 [0.28, 0.53]; p-value < 0.0001), representing a 61% reduction in the risk of disease progression or death for patients treated with DVd versus Vd.

From a safety perspective,

the addition of daratumumab was achieved without creating any new safety signal. Infections that occurred more frequently among the patients getting daratumumab resolved. The risk of Grade 3 or Grade 4 neutropenia, thrombocytopenia, or anemia was similar in both treatment arms, but there was a higher rate of pneumonia in patients treated with daratumumab (11% versus 4%).

Does this represent a new front-line standard of care?

While these data establish daratumumab-VPM as the new standard of care in transplant-ineligible patients in Europe and Latin America, whether the results will translate in the US, so to speak, is unclear because VPM is not the standard of care here. In order to address this, there are ongoing studies testing front-line daratumumab with other regimens for multiple myeloma.

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

The levels of immune cells within ovarian cancer tumors correlate with survival

Researches with the Ovarian Tumor Tissue Analyses Consortium analyzed the CD8+ (cytotoxic T-cell) content of tumors from 5,500 patients and compared them with clinical outcome. The analysis was large enough to allow for comparison by histologic subtype – endometrioid, clear cell, mucinous, and low-grade serous ovarian cancer, as well as high-grade serous ovarian cancer. Included in the sample were 3,200 high grade serous ovarian cancers. Continue reading

Pancreatic cancer – early detection, immune response, and infection-based resistance

Approximately 1.6 percent of men and women will be diagnosed with pancreatic cancer at some point during their lifetime. In 2014, an estimated 64,668 patients were living with the disease. The five-year survival for pancreatic cancer is 8.2% and it is projected to be the second leading cause of death due to cancer (behind lung cancer) in the US by the year 2030. For good reason, then, November is Pancreatic Awareness Month. Several recent research items are of particular interest to us. Continue reading