Day 3: August 8, 2018

CSC-Immune Cell Interactions Session

The session opened with an overview of effector T-cell activation and cancer immunotherapy. Junctional adhesion molecules, and specifically JAM-A, are important for maintaining barrier functions in the vasculature and the gut. In normal brain tissue, JAM-A is only expressed by microglia; however, for unknown reasons, JAM-A is present at high levels on cancer stem cells. It is also present at higher levels in glioblastomas and lower levels in low-grade gliomas.

High levels of JAM-A correlate with worse patient prognoses. Tumor cells with JAM-A suppressed by miRNA that were transplanted into immune-compromised mice were found to be poor tumor formers. Next were tumor transplant studies in JAM-A knockout mice. Kaplan-Meier survival curves showed much poorer outcomes for female knockout mice compared with wild-type female mice. A similar difference was not seen in male mice. Repeating this with castrated male mice again showed no difference, so it appears the difference may be driven by more than just sex hormones. Prognoses for human males with glioblastoma are generally worse than for females, and additional studies are underway to better understand the sex-specific differences in gliomas.

Keynote Address: Ned Sharpless

Dr. Norman “Ned” Sharpless, Director, National Cancer Institute, gave a keynote address, where he provided insights from his career as an academic oncologist through to where NCI is today, and where he hopes it will be in the future.

As a clinician he has long felt that the paradigm of active aging is clinically somewhat underexplored. For example, when a patient is treated, their cancer might be cured, but they are left physiologically older. Chemotherapy regimens also leave patients at increased risk of diseases of aging, and the increased risk appears to be lifelong: “The age state of hematopoietic stem cells induced by serial treatments with chemotherapy is molecularly similar to chronologic aging.” This has been shown in humans and in animal models.

He remarked that over the course of his research career, our understanding of the cell cycle has greatly improved and has provided insights into potential new therapeutic approaches. An example of this was the realization that, contrary to prior thinking, CDK4/6 is only important in certain cells and for certain proliferative events. It is not a “centerpiece” of the cell cycle, as was once thought.

This is important because it had initially been suggested that targeting CDK4/6 might have therapeutic benefits in cancers with an acceptable toxicity/safety profile. The practical outcome of this realization was the discovery of trilaciclib, a short-acting CDK4/6 inhibitor that preserves hematopoietic stem cells and immune system function during chemotherapy. Topline phase 2 data show myelopreservation in patients with newly diagnosed, treatment-naïve small cell lung cancer. It is also currently being studied for the treatment of triple-negative breast cancer.

Regarding the NCI, he stated: “…the first thing to notice is that this is a really good time in the United States to be doing cancer research.” There is “…broad bipartisan support for the National Cancer Institute at present…” and “…everybody seems to like the NIH in general and particularly the NCI.” He thinks that support comes from a belief by legislators that real progress is being made. Though legislators are not scientists, they see commercials on television about antibodies, they hear from constituents, and they know that President Jimmy Carter was cured with immunotherapy.

“They feel that their investment in cancer research is starting to pay off…” and that has translated into better funding after a decade of flat funding. If the draft budget is approved, the 2019 budget for NCI will be more than 6 billion dollars. Strategically the NCI is focusing on 4 key areas:

  • Workforce development – Focus on funding cancer researchers
  • Big data – Increase data aggregation, organization, and interpretation
  • Basic science – Reaffirm the commitment to basic science
  • Clinical trials – Development of innovative trial designs and execution of more trials

The 10 areas of the Cancer Moonshot initiative are also fully funded. Additional new initiatives include:

  • Cancer Immunotherapy Consortium
    • The goal is to “Establish a consortium of collaborating research teams to develop improved tumor-specific immunotherapy approaches.”
  • Human Tumor Atlas Network
    • To create, high-resolution maps of the dynamic 3-dimensional architecture of an individual tumor, that describe the molecular, cellular, and physiological events that occur within individual cancer cells, the cancer mass, the tissue of origin, and sites of metastasis, including the molecular, cellular, and soluble components that can influence the immune response to the cancer, in order to enable predictive modeling to refine therapeutic choices for patients
  • Developing a new cell therapy facility at the Frederick National Laboratory for Cancer Research
    • “Machines are bought. We’re starting to get the space up and running.”
    • The facility will manufacture T cells for NCI investigators to help overcome industry limitations and address the high demand for such cells

Metabolism and CSC Fate Decisions Session

Mitochondrial biology was the focus of the final scientific session of the conference. In addition to generating ATP and synthesizing macromolecules, mitochondria function as a signaling organelle. Specifically, the respiratory chain is essential for hematopoietic stem cell function, and when respiration is knocked out in vivo, tumors do not proliferate. Mitochondrial fission is essential for maintaining cellular homeostasis, but this is exacerbated in certain diseases, and clinically the need is to bring this process back into balance. Comparing mitochondrial fission in glioblastoma stem vs non-stem cells showed there is excessive fission in the stem cells.

Inhibitors of the proteins involved in the fission process are being investigated as potential therapeutic approaches. The BCL-2 family of proteins modulate the intrinsic apoptosis pathway, also known as the mitochondrial-mediated pathway. Studies are underway to examine whether the BCL-2 family is involved in maintaining mitochondrial fission in glioblastoma and to assess whether BCL-2 biomarkers can be identified in glioblastoma to better understand and treat these tumors.

Keynote Address: Normal and neoplastic stem cells

The closing presentation of the 2018 Cancer Stem Cell Conference was given by Dr. Irving Weissman from Stanford University. His basic premise was established with his opening words: “Stem cell biology is very, very simple. When a cell divides, if it’s a stem cell, of the 2 daughter cells on average one is still a stem cell; that’s it.”

The stem cells in animals or humans develop at the embryo-to-fetal transition in organogenesis, and all stem cells in living organisms are committed to making blood, brain, lung, or heart. There is no cross-over or trans-differentiation, no lineage reprogramming.

“We don’t have embryonic precursors of mesoderm, endoderm, ectoderm, trophoblasts; we have none of them. They are not self-renewing in the body; embryonic stem cells are an artifact of tissue culture.” That means that development of the system comes entirely from the hematopoietic stem cells; the blood and maintenance of the system come from stem cells. Therefore, if there is a malignant transformation or a blood disease develops, the first question that should be asked is, could this happen with stem cells?

Early attempts at hematopoietic cell transplantation to treat metastatic breast cancer following chemotherapy failed, with survival times in transplanted patients being no better than times for standard palliative care. The technology/clinical understanding of how to remove stem cells simply did not exist, so patients receiving the transplants were receiving more of their own cancer cells. Subsequently Dr. Weissman was able to isolate the first adult stem cell.

This built on his earlier mouse studies that identified Hoxb5 as the marker for the bone-marrow subpopulation of cells with long-term human stem cell capability, ie, able to provide full multilineage hematopoietic reconstitution.

He went on to describe the extensive research and significance of CD47, a tumor-associated antigen expressed on normal, healthy hematopoietic stem cells, which is overexpressed on the surface of a variety of cancer cells. Antibodies against CD47 have been shown to limit tumor growth in animal studies and are in clinical trials for multiple solid tumor and hematologic malignancies.

Another protein, calreticulin, appears on the surface of dying cells, especially those killed by immunogenic cell-death molecules and marks those cells for phagocytosis. Calreticulin is expressed by cancer cells and promotes phagocytosis, but if CD47 is expressed this is blocked, and the cancer cell is not cleared.

Both CD47 and calreticulin also appear to be important in other pathologies as they are found in atherosclerotic plaques. Mice lacking the ApoE gene who are fed a high-fat diet, but who are treated with an anti-CD47 antibody, do not develop the aneurysms and atherosclerotic plaques seen in animals where CD47 is not blocked. In this way, atherosclerosis looks like a precancerous tumor. The same is observed to be true for peritoneal adhesions.

Analysis of hematopoietic stem cells from patients with myelodysplastic syndrome show that almost all of them are abnormal. When these patients progress to AML, all of these cells were found to have CD47 on their surface. In this way, CD47 is apparently a general marker of a cell that is either dangerous or at the end of its life span.