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Advances in Cancer Immunotherapy

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Dramatic remissions in blood cancer in immunotherapy treatment trial

T cells are white blood cells that detect foreign or abnormal cells — including cancerous or infected cells — and initiate a process that targets those cells for attack. But the natural immune response to a tumor is often neither potent nor persistent enough, so Riddell and associates pioneered a new way to boost this immune response using a method known as “adoptive T-cell transfer.”

With adoptive T-cell transfer, immune cells are engineered to recognize and attack the patient’s cancer cells. Researchers extract T cells from a patient’s blood and then introduce genes into those T cells so they synthesize highly potent receptors (called chimeric antigen receptors, or CARs) that can recognize and target the cancer cell.

http://www.kurzweilai.net/images/20-million-T-cells.jpg

A single treatment of a relatively small number of the re-engineered T cells only takes about 30 minutes, and within weeks, the patient goes into a complete remission. (credit: Fred Hutchinson Cancer Research Center)

They grow the T cells in a laboratory for about two weeks and then infuse the engineered cells back into the patient, where they can home in on the tumor site and destroy the cancer cells.

Sustained remission of B cell cancers

Riddell’s team has recently developed a refined version of this process that increases the effectiveness of the immune response while reducing negative side effects, such as neurological symptoms, fevers, and large decreases in blood pressure.

In a study published in the journal Nature Biotechnology, Riddell and his team describe tagging the potent T-cell receptor (with amino acid sequences called Strep-tag), and the resulting effect on human cancer cells in the laboratory and on a mouse model of lymphoma.

Those results, using the latest version of this experimental immunotherapy, suggest sustained remission in cases of B cell cancers that previously relapsed and had become resistant to treatment.***

“The results are simply astounding,” Riddell said. We are treating patients with advanced leukemia and lymphoma that have failed every conventional therapy and radiation therapy, including transplants … in a single treatment. Within weeks, the patient goes into remission.”

“In my years as a oncologist and as a research scientist, I have never seen a treatment that has that spectacular response rate in its initial testing in patients,” Riddell said. His team is initiating trials in lung, breast, sarcoma, melanoma, and soon in pancreatic cancer. The opportunities for this technology are “incredible” and the approach has the potential to also treat common cancers such as kidney and colon cancer, he said.

“We are at the precipice of a revolution in cancer treatment based on using immunotherapy.”

Funding for Riddell’s research was provided by Juno Therapeutics.

* For approximately 100 years, the main tools to treat cancer were surgery, chemotherapy, and radiation therapy. But since around 2000, doctors have had access to a type of immunotherapy based on engineered antibodies that can target specific molecules on cancer cells. For example, trastuzumab (Herceptin) can be used for some types of breast cancer and stomach cancer. The new treatment approach used by Riddell’s team is based on a new type of immunotherapy using engineered immune cells to kill cancer, rather than antibodies.

** Stanley Riddell. Engineering T cells for safe and effective cancer immunotherapy. 2016 Annual Meeting of the American Association for the Advancement of Science, Washington, D.C., February 2016.

*** Such as acute lymphoblastic leukemia, Non-Hodgkin lymphoma, and chronic lymphocytic leukemia.

Abstract of Acquisition of a CD19 negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T cell therapy

Administration of lymphodepletion chemotherapy followed by CD19-specific chimeric antigen receptor (CAR)-modified T cells is a remarkably effective approach to treat patients with relapsed and refractory CD19+ B cell malignancies. We treated 7 patients with B-cell acute lymphoblastic leukemia (B-ALL) harboring rearrangement of the mixed lineage leukemia (MLL) gene with CD19 CAR-T cells. All patients achieved complete remission in the bone marrow by flow cytometry after CD19 CAR-T cell therapy; however, within one month of CAR-T cell infusion two of the patients developed acute myeloid leukemia that was clonally related to their B-ALL, a novel mechanism of CD19-negative immune escape. These reports have implications for the management of patients with relapsed and refractory MLL-B-ALL who receive CD19 CAR-T cell therapy.

Immunotherapy historically has involved all arms of the immune system in experimental treatments. That includes not only trained white blood cells, but B-cell antibodies and T-cell antibodies. In some experiments they attached poisons such as ricin to kill the cancer cells.Indeed most anti-cancer drugs can theoretically be attached to antibodies to kill of cancer cells specifically.Most approaches have had miraculous cures and remissions of hopelessly ill cancer patients who were dying.They are not offered to people who have no other hope except as small treatment studies.Why? Oncol;ogy is a big medical business, to cure it outright would put Oncologists out of work.The giant pharmaceutical companies that sell super expensive drugs would lose great gobs of money.They have some of the biggest lobbies in congress to maintain their business.
Often Immunotherapy of whatever form will have dangerous side effects.Some people do die from the treatments.It is unetihcal to refuse to give people who have a few weeks or minths to live a shot at these miracle treatments. In the case of enhanced T-cell therapy such as this one it can be difficult to control how extreme the body attacks. Today they have the means to put in genetic switches which will simply turn off the T-cells or any other cell line, by turning off the genes responsible for the action.One such switch is being produced by the company Intrexon using the insect molting hormone ecdysone to stop and start the genes of any organism.There almost certainly could be analogous techniques to biochemically create similar results if we understand how this one works.— I will be dead and gone a thousand years before any of this is cheaply available to the general population.

Despite the fact that immunotherapy has attracted considerable interest in recent years because of major progress in the identification of human tumor antigens (TA) suitable for clinical use, considerable obstacles to the development of clinically effective immunotherapy still exists including inability to:

induce expansion of large pools of antigen specific CD8+ T cells

maintain durable anti-tumor immunity > 5 years

overcome inherent tolerogenic mechanisms, such as CD4+CD25+ regulatory T cells (Tregs)

Unfortunately understanding the effectiveness of this new protocol with respect to resolving these obstacles takes time and future studies with larger cohorts.