Immune checkpoint inhibitors such as Keytruda and Opdivo work by unleashing the immune system’s T cells to attack tumor cells. Their introduction a decade ago marked a major advance in cancer therapy, but only 10% to 30% of treated patients experience long-term improvement. In a paper published online today in The Journal of Clinical Investigation (JCI), scientists at Albert Einstein College of Medicine describe findings that could bolster the effectiveness of immune-checkpoint therapy. Rather than rally T cells against cancer, the Einstein research team used different human immune cells known as natural killer (NK) cells—with dramatic results.

“We believe the novel immunotherapy we’ve developed has great potential to move into clinical trials involving various types of cancer,” said study leader Xingxing Zang, M.Med., Ph.D., Professor of microbiology  at Einstein and a member of the Cancer Therapeutics Program of the Montefiore Einstein Cancer Center.

You must be logged in to view this content.

Two patients with advanced Hodgkin lymphoma were told their tumors were
so resistant to treatment that hospice was their best option. Then, they were
enrolled in a clinical trial of a novel immunotherapy involving so-called
natural killer cells. After treatment, they saw complete remission.
Researchers say the results are a hopeful if preliminary sign of the potential of immunotherapies harnessing natural killer, or NK, cells — innate immune system cells that have certain advantages over the more commonly recognized adaptive T cell cancer therapies.
The treatment in the study, developed by the University of Texas MD Anderson Cancer Center and the German drug maker Affimed, combined offthe-shelf NK cells with a separate antibody that primes the cells to recognize a specific protein signature of the tumors. Two additional patients administered
the same treatment have shown ongoing partial responses.

“These results show you just how powerful NK cells are,” said Katy Rezvani,
a stem-cell transplant physician and NK cell researcher at MD Anderson, who
is spearheading the development of this new treatment.
“It’s amazing when you see these responses for patients who have so few
options, patients who’ve been told that they should go to hospice,” Rezvani
said.“I cannot begin to tell you how satisfying this is for clinicians.”
Data from the study is to be presented at the annual meeting of the American
Association for Cancer Research (AACR).
Source: https://www.mdanderson.org/
AND
https://www.mskcc.org/

“I’ll be honest, when I first started working on this I didn’t fully accept it.”
That’s Dr. Andrew Makrigiannis, head of the Department of Microbiology & Immunology at the Dalhousie University., discussing his groundbreaking research on natural killer cells that was published in the leading journal Proceedings of the National Academy of Sciences.“I’m a traditionally trained immunologist; I was skeptical”.
NK cells were originally discovered due to their novel ability to recognize and kill tumour cells without having previously encountered these aberrant cells, unlike other lymphocytes such as T and B cells.

One of the receptor families on NK cells which have been shown to play an important role in tumour recognition are the Ly49 receptor family.
Class I major histocompatibility complex (MHC-I) molecules are expressed on all nucleated cells and function as a marker of a “healthy” cell for NK cells. Ly49 receptor family recognition and binding to the host’s MHC-I molecule will signal to the NK cell not to kill this cell since it is healthy.

Alternatively, in transformed cells, such as those which are virally-infected or cancerous, MHC-I expression is reduced on the cell surface, and so, the NK cell now recognizes this cell as being an unhealthy cell. These cells are killed by the NK cell through various means such as direct cytotoxicity or indirectly through cytokine secretion and recruitment of other.

We observed that NK cells from mice with knocked-down expression of the Ly49 receptor family have defective killing of traditional tumour target cells which lack MHC-I expression in both in vitro [51Cr]-release cytotoxicity assays and in vivo rejection assays. Using different carcinoma models such as oncogene-driven lymphoma and carcinogen-induced sarcoma, we observed that mice with knocked-down expression of the Ly49 receptor family show defective tumour control. Specifically they are prone to earlier cancer development as well as metastatic formation. As well, through the use of antibodies and flow cytometry analysis of tumours isolated from Ly49-knock-down and wildtype mice, it was seen that there is differential expression of MHC-I. This observation suggests that tumours which grow in the knock-down mice are phenotypically different from those in the WT mice due to their altered immune environments which directly affect how these tumours develop.

Source: https://www.pnas.org/
AND
http://maklab.ca/