Biomaterial-delivered one-two punch boosts cancer immunotherapy

Date:
July 13, 2023
Source:
Wyss Institute for Biologically Inspired Engineering at Harvard
Summary:
In contrast to different blood cancers, the effectiveness of
adoptive T cell therapies in the treatment of solid tumors, which
comprise about 90% of all tumors, has been very limited because of
several formidable barriers. Now immune-engineers have developed a
novel biomaterials-based immunotherapy approach named SIVET that
has the potential to break down these barriers. The injectable
biomaterial enables both: the local delivery of antigen-specific
adoptively transferred T cells directly to tumor sites and their
prolonged activation, as well as a broader engagement of the
host immune system to provide much longer-lasting anti- tumor
effects against tumor cells carrying new antigens. Validated in
mice carrying melanomas, a particularly aggressive type of solid
tumor, SIVET enabled the fast shrinking of tumors and long-term
protection against them.


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==========================================================================
FULL STORY ========================================================================== Cancer immunotherapy has brought major improvement in patient survival
and quality of life, especially with the success of adoptive T cell and
immune checkpoint inhibitor therapies. Unfortunately, in contrast to
different blood cancers, the effectiveness of adoptive T cell therapies
in the treatment of solid tumors, which comprise about 90% of all tumors,
has been very limited because of several formidable barriers.

In adoptive T cell therapies, a patient's T cells with cytotoxic potential
are engineered outside the body so that they can bind specific features (antigens) on the surface of tumor cells, which converts them into tumor-killing cells.

However, after being reinfused into the donor patient's blood circulation,
they have to travel long distances to reach a solid tumor with only a
fraction of them ever arriving there. On-site, they need to infiltrate
the often difficult- to-penetrate tumor mass, while their cytotoxic
activity is suppressed by tumor cells and their surrounding tissue microenvironment. In addition, the further solid tumors grow, the more heterogenous their cell composition becomes, which also includes tumor
cells' repertoire of surface antigens, and thus allows them to "escape"
the attack of adoptively transferred T cells.

Now, a team of immune-engineers at the Wyss Institute for Biologically
Inspired Engineering at Harvard University and Harvard John A. Paulson
School of Engineering and Applied Sciences (SEAS) have developed a
novel biomaterials- based immunotherapy approach named SIVET (short for "synergistic in situ vaccination enhanced T cell") that has the potential
to break down these barriers. The injectable biomaterial enables both: the local delivery of antigen-specific adoptively transferred T cells directly
to tumor sites and their prolonged activation, as well as a broader
engagement of the host immune system to provide much longer-lasting
anti-tumor effects against tumor cells carrying new antigens. Validated in
mice carrying melanomas, a particularly aggressive type of solid tumor,
SIVET enabled the fast shrinking of tumors and long-term protection
against them. The findings are published in Nature Communications.

"In the SIVET approach, we essentially combined fast-acting adoptive
T cell therapy with long-term protective cancer vaccine technology in
a locally delivered integrated biomaterial. Advancing this approach
towards patient settings could help addresses several limitations of
current immunotherapies and offers new inroads into the treatment of
solid tumors," said senior author David Mooney, Ph.D., who is a Founding
Core Faculty member at the Wyss Institute and the Robert P. Pinkas Family Professor of Bioengineering at SEAS.

Mooney leads the Wyss Institute's Immunomaterials Platform and
co-leads the NIH-funded Immuno-Engineering to Improve Immunotherapy
(i3) Centercoordinated at the Wyss Institute and focused on creating biomaterials-driven approaches to enable anti-cancer immunotherapy in
solid tumor settings.

Biomaterial convergences In extensive previous work, Mooney's team had pioneered biomaterial-based cancer vaccines that are able to program key immune-orchestrating dendritic cells, known as antigen-presenting cells
(APCs), into tumor-fighting cells in vivo. Despite the cancer vaccines
being able to provide broad therapeutic and prophylactic benefits,
their tumor-directed effects take time to manifest in the body. On
the other hand, patient-specific adoptively transferred T cells are
ready-made to attack tumor cells upon first contact but produce rather short-lived responses.

"Our new platform fully leverages our expertise with adoptive T cell and
cancer vaccine technologies. Combining the best of these two worlds in
a multi-pronged biomaterial-based approach allows the fast debulking of existing tumor masses while engaging the immune system on a much deeper
level through the localized delivery, concentration, and activation
of diverse tumor-fighting immune cells," said co-first author Kwasi Adu-Berchie, Ph.D., who completed his Ph.D.

in Mooney's lab and is currently a Translational Immunotherapy Scientist
at the Wyss Institute.

Adu-Berchie, Mooney, and the team developed a cryogel biomaterial that
contains collagen and alginate polymers cross-linked into a 3-dimensional porous scaffold. While the alginate provides the biomaterial with
structural support, collagen serves to provide ligands needed for T cell trafficking. Following injection of the engineered T cell depot close
to a tumor site, the compressed biomaterial recovers its original shape
and starts releasing the cytokine interleukin 2 (IL2) to facilitate the expansion of the delivered T cells, which move out of the biomaterial
and onto the tumor to carry out an attack.

In addition, the biomaterial releases a second cytokine, abbreviated as
GMCSF, which attracts host APCs into the porous scaffold that then also
become concentrated and activated with the help of an adjuvant molecule
known as CpG close to the tumor. The activated APCs also infiltrate the
tumor mass where they take up new antigens created by dying tumor cells
that disintegrate as a result of the T cell attack. The APCs then migrate
to nearby lymph nodes where they orchestrate a broader vaccine response
by presenting processed antigens to other immune cell types, including
other cytotoxic T cells that attack the tumor in consecutive waves,
as well as memory T cells that stand by for future tumor recurrences.

The researchers investigated SIVET in a mouse model carrying melanoma
tumors and found that the multi-functional biomaterial enabled better
control over the tumors than the same adoptively transferred T cells
injected directly into the tumor site or infused into the blood stream of
the animals. SIVETs enabled the delivered T cells to remain active longer
and minimized the exhaustion of all T cells in the tumor microenvironment
when compared to control conditions.

"Through their vaccine component, SIVETs trained the immune system to
reject melanoma tumors for significantly prolonged periods of time, and
thus allowed the animals to survive for significantly longer than animals
that received any of our control treatments. This likely was facilitated
by the biomaterial's ability to prevent the growth of tumor cells that
escape the attack of adoptively transferred T cells due to their loss
of the initially targeted antigen," said Adu-Berchie. "Identifying a tumor-specific antigen against which potent donor-specific T cells can
be generated for adoptive transfer could provide SIVETs with enough to
go on to initiate a tumor attack on a much broader front and scale.

"This study is a beautiful convergence of two powerful immunotherapy
approaches that are programmed in the body to synergize with each
other. This work once again demonstrates the power of taking an
unconventional trans-disciplinary approach -- in this case, combining strategies from materials science and tissue engineering with immunology
-- to create novel and more powerful therapeutics for the eradication of
solid cancers," said Wyss Founding Director Donald Ingber, M.D., Ph.D.,
who is also the Judah Folkman Professor of Vascular Biology at Harvard
Medical School and Boston Children's Hospital, and the Hansjo"rg Wyss
Professor of Bioinspired Engineering at SEAS.

The study is also authored by other past and present members of
Mooney's group, including Joshua Brockman, Yutong Liu, Tania To, David
Zhang, Alexander Najibi, Yoav Binenbaum, Alexander Stafford, Nikolaus Dimitrakakis, Miguel Sobral, and Maxence Dellacherie. It was supported by grants from the National Institutes of Health (award #U54 CA244726 and
#U01 CA214369), National Science Foundation (award #MRSEC DMR-1420570),
and Food and Drug Administration (award #R01 FD006589), as well as the
National Cancer Institute (award #5K00CA234959).

* RELATED_TOPICS
o Health_&_Medicine
# Brain_Tumor # Cancer # Lung_Cancer # Immune_System #
Lymphoma # Skin_Cancer # Colon_Cancer # Ovarian_Cancer
* RELATED_TERMS
o Monoclonal_antibody_therapy o Cancer o T_cell o Brain_tumor
o Immune_system o Tumor_suppressor_gene o Natural_killer_cell
o BRCA1

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Story Source: Materials provided
by Wyss_Institute_for_Biologically_Inspired_Engineering_at
Harvard. Original written by Benjamin Boettner. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Kwasi Adu-Berchie, Joshua M. Brockman, Yutong Liu, Tania W. To,
David K.

Y. Zhang, Alexander J. Najibi, Yoav Binenbaum, Alexander Stafford,
Nikolaos Dimitrakakis, Miguel C. Sobral, Maxence O. Dellacherie,
David J.

Mooney. Adoptive T cell transfer and host antigen-presenting cell
recruitment with cryogel scaffolds promotes long-term protection
against solid tumors. Nature Communications, 2023; 14 (1) DOI:
10.1038/s41467- 023-39330-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/07/230713142018.htm

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