Clinician-to-Clinician Update Clinician-to-Clinician Update

Exploiting the Immune Response to Treat Patients With Cancer

May 2016

Contributed by Jeffrey Miller, M.D.

The success of allogeneic (using donor cells) bone marrow transplant is dependent on three factors:

  • Chemotherapy and radiation therapy
  • Engraftment of new bone marrow stem cells from the donor
  • Permanent immune differences between the donor and recipient such that reconstituted donor lymphocytes help fight recipient cancer recurrence (a process referred to as a “graft-versus-leukemia” or GvL effect)

The third factor is perhaps the oldest and best-established strategy to prove the power of the immune response in cancer therapy. This form of immunotherapy is mediated by donor immune lymphocytes and has been a platform to dissect immune components to develop better cancer therapies.

All humans, healthy or not, have cells called “natural killers” that help make up our immune systems. These white blood cells make up 10-15 percent of lymphocytes and are very different from T or B-cell lymphocytes. When cells become damaged, infected, or cancerous, NK cells recognize changes on those cells and kill them. They naturally mediate this function without activation or prior immunization.

So, for people with cancer that continues to grow, why don’t NK cells destroy the tumors? The answer is complicated because when tumors start to grow, they suppress the immune system. There’s no way to know how many times NK cells protect someone from cancer. We only know when they fail and cancer cells grow large enough to become symptomatic.

Jeffrey-Miller-Metro-Doctors
— Jeffrey Miller, MD



At the Masonic Cancer Center, University of Minnesota, we’re studying NK cells and how best to use them in cancer therapies and have recently discovered new ways NK cells can be activated and directed to seek and destroy tumor cells.

In the past nearly 25 years, we have been exploring what capacity NK cells have to become cancer scavengers. We’ve treated more than 300 patients in clinical trials since then and have definitely had success. We started these investigations in 1994 treating lymphoma and breast cancer patients after autologous (using the patient’s own stem cells) bone marrow transplant. We gave these patients drugs called interleukins (IL-2) to expand NK cells in the body in hopes of preventing relapse, which occurs in the 25 percent of patients undergoing this procedure. We found that IL-2 alone was ineffective to fully activate NK cells to kill cancer. This led to our first cell therapeutic trial where autologous NK cells were taken out of the body and activated with highconcentrations of IL-2. Even though we could induce better immune function in the body, we were still not happy with outcomes and relapses continued to occur.

It was not until the late 1990s that we also discovered that patient NK cells are suppressed by their own tumor through special receptors that recognize “self” molecules and turn off NK cell function. Therefore, NK cells from a related donor can overcome this inhibition and more effectively kill cancer cells. In 2000, this biologic breakthrough led us to start using donor NK cells from family members.

NK cells are given to patients after what is called “lymphodepleting chemotherapy regimen” that makes space for new cells and alters the endogenous cytokine milieu (promotes interleukins in the body) to promote the survival of NK cells and their expansion in the body after donor NK cell infusion. In one clinical trial, for instance, we infused patients afflicted with resistant or relapsed acute myeloid leukemia (AML), a setting where salvage chemotherapy only works <10 percent of the time, with NK cells from a healthy donor and saw a 30-40 percent remission rate — definitely a positive outcome.

We also have ongoing studies in patients with advanced lymphoma and late stage ovarian cancer. What we know is that we can put stubborn cases of various cancers into remission, and now we’re trying to re-purpose different receptors on the NK cells to get a higher percentage of patients into longer-lasting remission.

We currently have an open clinical trial for women who have ovarian cancer, which involves infusing donor NK cells directly into the patients’ abdominal cavities instead of into the bloodstream as we did with leukemia.

We’re hoping we can improve the outcomes by putting NK cells into close proximity to the cancer. The goal for the study is to find the donor NK cells in the patient’s blood after seven or 14 days. If we can detect them in a blood test, we know the infused NK cells have expanded successfully.

Like most clinical trials, the ovarian cancer study is expensive, so right now the team is starting with one infusion per patient. But if the results indicate that it’s a successful therapy for ovarian cancer, future plans may involve infusions every three months for the first year of treatment.

Team Science

What we’ve built at the University is a “team science” approach: developing a critical mass of investigators focused on one area of research. We have a team of 20-plus researchers, including University of Minnesota Medical School faculty and staff, laboratory workers, students and postdoctoral fellows focused on immunotherapies. To make sure everyone stays abreast of work going on in other labs, we hold regular meetings and present clinical trial results to keep the lab team excited about what it’s doing. It is the talent of the collective group that keeps us on top of a very complicated field.

It’s important to build on our expertise to bring something meaningful to the cancer community. NK cell research is one of the Masonic Cancer Center’s specialties. Under that NK cell research umbrella, the scientists investigate separate but related projects. Major projects underway include the use of donor NK cells, typically from a half-matched family member, and studying the roles of different receptors on NK cells. Another project involves the cultivation of NK cells from human pluripotent stem cells, where our researchers developed a more efficient, cost-effective process for deriving NK cells from stem cells, which could pave the way for a larger-scale production effort.

Fine-Tuning the Formula

We have made exciting new discoveries in lab and have learned from 20 years of experience using NK cells to treat patients with cancer. We are focused on two major themes, which will drive our efforts for the next several years.

BiKEs and TriKEs: The first path is based on the goal of making NK cells specific to recognize different tumors. In collaboration with basic scientist Daniel Vallera, we have been able to produce Bi- or Tri-specific Killer Engagers (we call them BiKEs and TriKEs), which juxtapose NK cells and cancer targets to enhance clinical efficacy and overcome tumor inhibition.

Virus activation to induce “adaptive NK cells” with specialized function:

The second area of focus is to make better NK cell infusions by building on a new discovery that viruses (such as cytomegalovirus) can prime NK cells and induce them to acquire properties of immunologic memory. In bone marrow transplant patients, having high numbers of these “adaptive NK cells” leads to less relapse. Our goal is to grow these cells for infusion into patients with cancer and we hope to test a new cell product by 2017.

With each new discovery, our team develops a better understanding of how NK cells can be manipulated to attack and kill cancer cells; then we tinker with the formula and try again.

To see a list of current open clinical trials at the University of Minnesota, including the trials mentioned in this article, visit the Masonic Cancer Clinic clinical trials website. You can also subscribe to our M Health Cancer Care quarterly physician newsletter to keep informed about program updates, new treatments and clinical trials.

Article appears in MetroDoctors. 2016;18(1):24-25. MetroDoctors is the journal of the Twin Cities Medical Society.

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