Fighting cancer with rejection-resistant, 'off-the-shelf' therapeutic T
cells

Date:
August 20, 2020
Source:
Baylor College of Medicine
Summary:
Researchers are developing ready-to-use, off-the-shelf therapeutic
T cells. These are genetically engineered T cells that are
manufactured from normal, healthy donors. The cells are expanded
and well characterized, and have shown to be effective at killing
cancer cells.



FULL STORY ========================================================================== Personalized cancer treatments are no longer just options of the
future. In the past few years, researchers have made significant progress
in 'teaching' the body's immune T cells to recognize and kill specific
cancer cells, and human clinical trials have shown that this approach
can successfully eliminate tumors.


========================================================================== Cancer patients today can be a part of the following clinical scenario:
a patient comes to the hospital where physicians and scientists analyze
his or her tumor to identify cancer-specific markers that would serve
as targets for the novel therapy. Blood is drawn from the patient and
sent to Baylor College of Medicine's Center for Cell and Gene Therapy
where the immune T cells are transformed into cells with a mission to
identify and kill cells with the tumor-specific tags. The final cells
are infused back into the patient to complete their job.

"At the Center, we genetically engineer the patient's T cells to arm
them with the tools they need to identify the patient's tumor-specific
markers and eliminate the cancer," said Dr. Maksim Mamonkin, assistant professor of pathology & immunology and member of the Center for Cell
and Gene Therapy at Baylor.

Although this treatment can effectively eliminate tumors, the 'training'
of the T cells is complex and expensive. "Sometimes, the trained T cells
are not highly potent because the patient already received a number of treatments that weakened the immune cells we work with," Mamonkin said.

In addition, the process to manufacture the therapeutic T cells is time consuming. "Sometimes it takes weeks to get the T cells ready, and in
this time the patient may take a turn for the worse," Mamonkin said.

The next step: off-the-shelf therapies "Now that we know that this
type of cell immunotherapy has a lot of promise, the next step is to
streamline it, make it more accessible and make sure that the resulting
T cells have the highest potency," said Mamonkin, who also is a member
of the Dan L Duncan Comprehensive Cancer Center.



========================================================================== Researchers are developing ready-to-use, off-the-shelf therapeutic
T cells.

These are genetically engineered T cells that are manufactured from
normal, healthy donors. The cells are expanded and well characterized,
and have shown to be effective at killing cancer cells. The cells are cryo-preserved -- stored frozen in liquid nitrogen -- until it's time
to use them. In this scenario, a cancer patient comes to the hospital
and the tumor markers are identified.

Then, with the identity of the tumor-specific tags in hand, the physician
goes to a room filled with large below-zero freezers searching for the one
that holds little containers with healthy immune T cells that have been genetically engineered to recognize and destroy cells with the patient's cancer-specific markers. These 'off-the-shelf,' ready-made cells are
thawed, prepared and infused into the patient several days later.

"This approach solves two limitations of the original approach: it
avoids the time-consuming, elaborate steps of training and expanding the patient's cells and results in therapeutic T cells of higher potency,"
Mamonkin said. "However, the novel approach presents a new set of
limitations." Dealing with rejection One of the limitations of the off-the-shelf approach emerges when the therapeutic T cells enter the
patient's body. The patient's own immune system recognizes the cells as foreign, such as it happens with organ transplants, and may reject the therapeutic cells.

"This is a major problem because rejection not only would reduce the
duration of the T cells activity against the tumor, but also would
preclude giving subsequent doses of cells. The immune system would reject subsequent doses of the cells right way," said first author, Feiyan Mo, graduate student in Mamonkin's lab. "To solve this problem we thought
that the best defense was a good offense." The researchers gave the
therapeutic T cells a tool that would enable them to fight back the attack
of the patient's immune cells against them. They genetically engineered
the therapeutic T cells to express a receptor called alloimmune defense receptor, or ADR. ADR recognizes a specific molecule, called 4-1BB, that
is only expressed on the patient's activated T cells and natural killer
(NK) cells that would attack them. 4-1BB is not expressed on resting T
and NK cells that do not turn against the therapeutic T cells.



========================================================================== "Both experiments in the lab and animal models with blood cancers or solid tumors showed that ADR protected off-the-shelf therapeutic T cells from
being rejected," Mo said. "Not only did they resist rejection, but they
also expanded more and persisted longer than therapeutic T cells without
ADR." The researchers are optimistic that this approach may also work
in patients. They plan to conduct clinical trials on 2021.

Beyond cancer applications "If successful, this approach can be extended
to targeting other disease- causing T-cells, such as those rejecting transplanted organs, mediating graft- versus-host disease or perpetuating autoimmunity," said Mamonkin. "We are very excited to develop this concept
for several applications beyond cancer therapy." This technology has
been licensed to Fate Therapeutics, a clinical- stage biopharmaceutical
company that plans on integrating ADR into their clinical products.

"The BCM Ventures team is very pleased to partner with Fate Therapeutics
in a licensing relationship to support their implementation of the ADR technology developed in the Mamonkin laboratory here at BCM. This approach promises to enhance the effectiveness of off-the-shelf cell therapies, and
it will now be used more extensively in the clinical setting which stands
to benefit patients," said Michael Dilling, director of Baylor Licensing
Group. "BCM has been an innovator in the development of cell therapies
and the commercial sector increasingly looks to BCM as a source for new innovations." Feiyan Mo, who took the lead on this work, has received
an NIH NCI F99/F00 Predoctoral-to-postdoctoral Fellowship Award to help facilitate the translation of ADR to the clinic and continue postdoctoral studies in cancer biology. She is a Baylor graduate student and is
co-mentored by Drs. Mamonkin, Malcolm Brenner and Helen Heslop. Details
of this work can be found in the journal Nature Biotechnology.

Other contributors of this study include Feiyan Mo, Norihiro Watanabe,
Mary K.

McKenna, M. John Hicks, Madhuwanti Srinivasan, Diogo Gomes-Silva,
Erden Atilla, Tyler Smith, Pinar Ataca Atilla, Royce Ma, David Quach,
Helen E. Heslop and Malcolm K. Brenner. The authors are affiliated with
one of more of the following institutions Baylor College of Medicine,
Texas Children's Hospital and Houston Methodist Hospital.

This project was supported by the Leukemia and Lymphoma Society
Translational Research Award no. 6566, NIH NCI SPORE in Lymphoma
5P50CA126752, SU2C/AACR 604817 Meg Vosburg T cell Lymphoma Dream Team,
Gloria Levin Fund and CPRIT Award nos. RP180810 and RP150611. Stand
Up To Cancer is a program of the Entertainment Industry Foundation
administered by the American Association for Cancer Research. The Dan
L Duncan Comprehensive Cancer Center also provided support through its
shared resources (P30 CA125123).


========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Original written by Ana Mari'a Rodri'guez, Ph.D.. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Feiyan Mo, Norihiro Watanabe, Mary K. McKenna, M. John Hicks,
Madhuwanti
Srinivasan, Diogo Gomes-Silva, Erden Atilla, Tyler Smith, Pinar
Ataca Atilla, Royce Ma, David Quach, Helen E. Heslop, Malcolm
K. Brenner, Maksim Mamonkin. Engineered off-the-shelf therapeutic
T cells resist host immune rejection. Nature Biotechnology, 2020;
DOI: 10.1038/s41587-020- 0601-5 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200820143825.htm

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