Page 11 - Read Online

Bhasin et al. J Transl Genet Genom 2024;8:55-76 https://dx.doi.org/10.20517/jtgg.2023.46 Page 59

TUMOR-ASSOCIATED ANTIGENS FOR T-CELL REDIRECTING THERAPIES
Despite its limited clinical success in prostate cancer, ICI therapy provided fundamental insight into the
therapeutic potential of T-cell immune modulation and ushered in a new era of immunotherapies.
Bispecific T-cell engager (BiTE) and chimeric antigen receptor therapies (CAR-T) are two classes of T-cell-
[26]
directed immunotherapies under rapid development . In contrast to ICIs, BiTE and CAR-T are MHC-
[27]
independent classes of therapy that are designed to target a specific tumor-associated antigen (TAA) .
These therapies have immense potential to dramatically impact the treatment of prostate cancer and
overcome barriers that have limited the efficacy of ICIs [Figure 1].
[28]

BiTEs are genetically engineered recombinant proteins with two unique single-chain variable fragments
(scFvs), each with a specific monoclonal antibody. One binding region targets the CD3 region of T-cells,
while the other is engineered to target a particular TAA of interest. It is important to note that this
configuration allows for T-cell activation independent of the T-cell receptor-MHC pathway and
circumvents a common evasion mechanism of cancer cells [27,29-32] . Simultaneous binding induces a
downstream cytolytic signaling cascade, which creates the formation of a synapse between the T-cell and the
target tumor cell. Subsequently, T-cells release granzymes, perforins, and cytokines, inducing cellular
apoptosis of the cancer cell . Furthermore, local release and diffusion of cytokines induce the upregulation
[33]
of cell surface molecules on TAA-negative cells, namely the FAS death receptor, triggering further T-cell
mediated lysis of tumor cells in a process termed the “bystander effect” [33,34] .

CAR-T therapy is a synthetically designed receptor that is composed of three primary elements, which
include an extracellular scFv with an antigen receptor specifically designed to a TAA of interest, a
transmembrane domain that anchors the CAR to the T-cell membrane, and the signal transduction domain
that initiates the intracellular signaling cascade within the T-cell (via CD3 and costimulatory CD28) to
promote T-cell activation, proliferation, and targeted cell death. This process also occurs independently of
the MHC/TCR complex [35-38] . Unlike BiTEs, CAR-T cell production is a process that is personally engineered
for each individual patient, with several steps needed prior to administration. The process involves
leukapheresis to isolate a patient’s T-cells, T-cell selection, transduction of these cells via a designed vector
to express the CAR, expansion of the CAR-T population with growth factors, and lymphodepletion of
patients prior to administration [38,39] . Once administered, the mechanism of action of CAR-T is very similar
to that of a BiTE therapy, as the CAR-T molecules bind to a TAA of interest. Thereafter, cellular apoptosis is
induced with the subsequent release of granzymes, perforins, and cytokines that results in sensitization of
the local tumor microenvironment (TME) which has the potential to alter the immune milieu [28,35,36,40] .
Despite CAR-T therapy’s revolutionary impact on hematologic malignancies, no CAR-T therapies have
been approved for the treatment of solid tumor malignancies.

There is a strong biologic rationale for the employment of BiTEs and CAR-T immunotherapy in prostate
cancer. MHC-independent T-cell activation avoids prostate cancer’s unique ability of MHC class I
downregulation, along with its ability to prevent MHC interactions due to immunosuppressive alterations
of the local TME. The immunologically “cold” TME allows prostate cancer to evade immunosurveillance
and allows for continued tumor growth. However, novel immunotherapies may enhance immune cell
infiltration and activation within the TME through local immunoactivation, converting the TME into a
“hot” immunogenic tumor.

Clinical studies of BiTE and CAR-T therapies have demonstrated several safety concerns. Many of the
established adverse effects of T-cell redirecting therapies are drawn from observations recorded from the
treatment of hematologic malignancies. Notable adverse effects seen in these treatment modalities include