Normal and Neoplastic stem cells
HYBRID FORMAT - https://us06web.zoom.us/j/89366203814?pwd=ZGxocXJ5VzZIMDYxcFh5bHFTeFpVZz09
Stem cell isolation and transplantation is the basis for regenerative medicine. We isolated mouse then human hematopoietic stem cells (HSCs). The purified HSC are depleted of T cells, and if taken from cancer patients, depleted of cancer cells. Cancer-free autologous HSC rescue patients with metastatic breast cancer from myeloablative high dose combination chemotherapy with much better median survival and 25 year overall survival that with cancer contaminated mobilized blood, or any current therapy. Importantly, the allogeneic transplantation of purified HSCs results in complete regeneration of the blood and immune systems without causing graft vs, host disease, and can induce permanent transplant tolerance of any organ or cell from the HSC donor. HSC transplantation offers a curative treatment for a wide range of hematological and immune disorders, however the main barrier to a broad clinical application is the high toxicity of current conditioning regimens. To make HSC transplantation a safe, well-tolerated procedure, our group has been developing antibody-based non-toxic conditioning methods to replace chemotherapy and radiation.
To study the relationship between stem cells and cancer, we followed the preleukemic progression from HSCs to myelogenous leukemias and found that the developing pre-cancerous HSC clones gradually accumulate mutations, with the last mutation giving rise to leukemia stem cells (LSC). While the mutations arise randomly, in the precancer HSC clone the order of mutations is nonrandom. The LSCs are downstream oligolineage or multilineage progenitors that have acquired self-renewal and evaded programmed cell death and programmed cell removal.
A checkpoint inhibitor for innate immunity macrophages: By comparing LSC to HSC, we identified CD47 overexpression on LSC, and then on all cancers tested, and showed that it is a cell surface molecule used by live cancer cells to evade macrophage phagocytosis by binding to SIRP, its inhibitory receptor on macrophages. CD47 is the first target that is expressed on all human cancers tested. Humanized clinical grade IgG4 anti-CD47 Abs are in phase 1/2 clinical trials. anti-CD47 combination with Rituximab led to responses in patients with highly aggressive lymphomas who were relapsed and refractory to Rituxan and chemotherapy (Advani et. al, 2018 NEJM). The combination of anti-CD47 and azacytidine in high risk MDS patients gave an overall response rate of 92%, 50% complete remission; in untreated AML the ORR was 64% with 41% CR.
Date:
5 May 2022, 14:30 (Thursday, 2nd week, Trinity 2022)
Venue:
Sir William Dunn School of Pathology, South Parks Road OX1 3RE
Venue Details:
EPA Seminar Room
Speaker:
Prof Irv Weismann (Stanford Institute for Stem Cell Biology and Regenerative Medicine)
Organising department:
Sir William Dunn School of Pathology
Organiser:
Melissa Wright (Sir William Dunn School of Pathology)
Organiser contact email address:
melissa.wright@path.ox.ac.uk
Host:
Prof Simon Hunt (Sir William Dunn School of Pathology)
Part of:
Dunn School of Pathology Research Seminars
Booking required?:
Not required
Audience:
Members of the University only
Editor:
Melissa Wright
