Page 1075 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1040 ParT EighT Immunology of Neoplasia

to assess the safety and immunoregulatory activity of urelumab
(BMS-663513) in patients with advanced and/or metastatic Adoptive Immunotherapy With Genetically
tumors and relapsed/refractory B-cell non-Hodgkin lymphoma Modified Lymphocytes
are under investigation (ClinicalTrials.gov). In early 2000, studies demonstrated that genetically engineered
lymphocytes transduced with a retrovirus encoding a TCR to
OX40 (CD134) recognize melanoma-melanocyte antigen (MART-1) could
OX40 (CD134) is expressed on activated T cells, including mediate tumor regression. 53
activated effector and Tregs. Engagement of OX40 with its ligand To improve the T-cell antigen specificity, a new class of
enhances proliferation and survival of T cells. Preclinical studies “chimeric antigen receptor” (CAR) was developed. This model
with OX40 have shown increased antitumor responses and overall was capable of overcoming limitations associated with central
survival. A trial with the murine anti-OX40 agonist 9B12 mAb and peripheral tolerance, generating efficient T cells. The advan-
in patients with advanced cancers was well tolerated and dem- tage of CAR compared with conventional TCR is that the antigen
onstrated regression of at least one metastatic lesion in 12 out need not be processed and presented by MHC. Importantly, this
51
of 30 patients. Humanized antibodies against OX40 are under approach can be used in all patients who express the same tumor
clinical development. A phase I first-in-human study to evaluate antigen, regardless of HLA type. 53,54
the anti-OX40 antibody GSK3174998 as monotherapy and in
combination with anti-PD-1 therapy (pembrolizumab) in patients Clinical Development of Chimeric Antigen Receptor
with advanced solid tumors is ongoing (ClinicalTrials.gov). In T Cells
addition, a phase Ib dose escalation study of the anti-OX40 Chimeric antigen receptor T cells (CAR T cells) are defined as
antibody MOXR0916 plus the anti-PD-L1 antibody atezolizumab T cells that are genetically modified to express an artificial
is ongoing in patients with locally advanced or metastatic solid construct, consisting of a synthetic TCR targeted at a predeter-
tumors (ClinicalTrials.gov). mined antigen expressed on tumor cells.
Coupling the CAR construct, which typically consists of a
ADOPTIVE CELL TRANSFER single-chain variable fragment (scFv; directed against a known
tumor antigen), with the aid of a linker and a spacer to the
Several clinical studies have demonstrated that the reinfusion transmembrane domain and a CD3ζ signaling domain, which
of autologous lymphocytes in cancer patients, isolated from their provides “signal 1” necessary for T-cell activation, paved its way
own tumor or peripheral blood, could inhibit tumor growth, as first-generation CAR T cells. Preclinical studies using first-
and these initial studies formed the basis for adoptive T-cell generation CAR T cells directed against CD19 expressing B-cell
therapy. 52 malignancies and HER2/Neu showed promising results. 55
For adoptive immunotherapy, the isolation of antigen-specific After this success, the second-generation CAR T cells were
T cells from the peripheral blood or tumor is followed by clonal developed by coupling the intracellular portion of the construct
expansion and transfusion back into the tumor-bearing host. with additional costimulatory signaling domains such as CD28
Adoptive T-cell transfer has achieved tumor regression and or 4–1BB, which provided “signal 2” for T-cell activation and
improved survival by increasing the number of reactive T further improved the efficacy of CAR T cells.
cells, providing long-term immune protection and guaranteeing
antigen specificity. The downside to this method is both the KEY CONCEPTS
expense and the expertise needed to perform this labor-intensive
therapy. Assuming that the T cells are already primed to the Chimeric Antigen Receptor (CAR) T Cells
tumor and are antigen-specific, they can be polyclonally activated Synthetic Receptor
ex vivo before being reinfused back into the patient. Suppressing
the immune system before adoptive transfer is important for • Single-chain variable fragment
• Linker and a spacer to the transmembrane domain
improving the antitumor efficacy. Significant progress has been • CD3ζ signaling domain
made to establish adoptive T-cell therapy as a standard-of-care • Additional costimulatory signaling domains
method for the treatment of cancer, and multiple studies are
ongoing. 53
Further optimization led to the development of the
Adoptive Transfer of Tumor-Specific Cytotoxic T Cells third-generation CAR T cells, which incorporated two-tandem
Studies in murine tumor models have demonstrated that the costimulatory domains by coupling ICOS, CD27, CD28, 4–1BB,
lymphocytes in transplantable tumors are capable of recognizing or OX40 (e.g., CD28/4–1BB/CD3ζ or CD28/OX40/CD3ζ), hence
tumor cells in vitro, and the adoptive transfer of these syngeneic demonstrating varying degrees of in vitro and in vivo T-cell activa-
tumor-infiltrating lymphocytes (TIL) could mediate tumor tion, proliferation, and cytokine (interleukin [IL]-2) production. 55
regression in certain cancers. In vitro studies demonstrated that The armored CAR T represent the next-generation CAR T
TIL obtained from melanoma patients could specifically recognize cells, which incorporate not only the two-costimulatory domains
autologous tumors. Further studies based on this observation but also an additional transgene for cytokines (e.g., IL-12) or
demonstrated that transfer of autologous TIL could mediate ligands (e.g., CD40L or 4–1BBL); this helps these CAR T cells
objective regression in patients with metastatic melanoma and to survive and/or disrupt an immunosuppressive tumor micro-
53
across other cancers. An alternative source of endogenous environment. 53,55 The key concepts of the four generations of
tumor-reactive T cells can be found in the peripheral blood of CAR T cells are illustrated in Fig. 77.5.
patients. Strategies to isolate and expand these rare circulating CTL019 is the first investigational CAR T to receive
T cells are being developed for further investigation in clinical breakthrough-therapy status by the FDA for the treatment of
trials to target a broader population of patients. 54 adult and pediatric relapsed/refractory acute lymphoblastic