The therapy of solid tumors has been revolutionized by immune therapy, in particular,
approaches that activate immune T cells in a polyclonal manner through blockade of checkpoint
pathways such as PD-1 by administration of monoclonal antibodies. In this study, we will
evaluate the adoptive transfer of RAPA-201 cells, which are checkpoint-deficient polyclonal T
cells that represent an analogous yet distinct immune therapy treatment platform for solid
tumors.
RAPA-201 is a second-generation immunotherapy product consisting of reprogrammed autologous
CD4+ and CD8+ T cells of Th1/Tc1 cytokine phenotype. First-generation RAPA-101, which was
bred for resistance to the mTOR inhibitor rapamycin, demonstrated clear anti-tumor effects in
multiple myeloma patients without any product-related adverse events. Second-generation
RAPA-201, which have acquired resistance to the mTOR inhibitor temsirolimus, are manufactured
ex vivo from peripheral blood mononuclear cells collected from solid tumor patients using a
steady-state apheresis. RAPA-201 is also being evaluated for the therapy of relapsed,
refractory multiple myeloma and was granted Fast Track Status by the FDA for this indication.
The novel RAPA-201 manufacturing platform, which incorporates both an mTOR inhibitor
(temsirolimus) and an anti-cancer Th1/Tc1 polarizing agent (IFN-alpha) generates polyclonal T
cells with five key characteristics:
1. Th1/Tc1: polarization to anti-cancer Th1 and Tc1 subsets, with commensurate
down-regulation of immune suppressive Th2 and regulatory T (TREG) subsets;
2. T Central Memory: expression of a T central memory (TCM) phenotype, which promotes T
cell engraftment and persistence for prolonged anti-tumor effects;
3. Temsirolimus-Resistance: acquisition of temsirolimus-resistance, which translates into a
multi-faceted anti-apoptotic phenotype that improves T cell fitness in the stringent
conditions of the tumor microenvironment;
4. T Cell Quiescence: reduced T cell activation, as evidence by reduced expression of the
IL-2 receptor CD25, which reduces T cell-mediated cytokine toxicities such as
cytokine-release syndrome (CRS) that limit other forms of T cell therapy; and
5. Reduced Checkpoints: multiple checkpoint inhibitory receptors are markedly reduced on
RAPA-201 cells (including but not limited to PD-1, CTLA4, TIM-3, LAG3, and LAIR1), which
increases T cell immunity in the checkpoint-replete, immune suppressive tumor
microenvironment.
This is a Simon 2-stage, non-randomized, open label, multi-site, phase I/II trial of RAPA-201
T immune cell therapy in patients with advanced metastatic, recurrent, and unresectable solid
tumors that have recurred or relapsed after prior immune therapy. Patients must have tumor
relapse after at least one prior line of therapy and must have refractory status to the most
recent regimen, which must include an anti-PD-(L)1 monoclonal antibody. Furthermore, accrual
is limited to solid tumor disease types potentially amenable to standard-of-care salvage
chemotherapy consisting of the carboplatin + paclitaxel (CP) regimen that will be utilized
for host conditioning prior to RAPA-201 therapy. Importantly, carboplatin and paclitaxel are
"immunogenic" chemotherapy agents whereby the resultant cancer cell death mechanism is
favorable for generation of anti-tumor immune T cell responses. Thus, the CP regimen that
this protocol incorporates is intended to directly control tumor progression and indirectly
promote anti-tumor T cell immunity. The CP regimen is considered standard-of-care therapy for
the following tumor types, which will be focused upon on this RAPA-201 protocol: small cell
and non-small cell lung cancer; breast cancer (triple-negative sub-type or relapse after
ovarian ablation/suppression); gastric cancer (esophageal and esophageal-gastric-junction
adenocarcinoma; gastric adenocarcinoma; esophageal squamous cell carcinoma); head and neck
cancer (squamous cell carcinoma of oral cavity, larynx, nasopharynx, and other sites);
carcinoma of unknown primary; bladder cancer; and malignant melanoma.
Protocol therapy consists of six cycles of standard-of-care chemotherapy (carboplatin +
paclitaxel (CP) regimen) administered every 28 days (chemotherapy administered on cycles day
1, 8, and 15). RAPA-201 cells will be administered at a target flat dose of 400 X 10^6 cells
per infusion on day 3 of cycles 2 through 6.
A sample size of up to 22 patients was selected to determine whether RAPA-201 therapy, when
used in combination with the CP regimen, represents an active regimen in solid tumors that
are resistant to anti-PD(L)-1 checkpoint inhibitor therapy, as defined by a response rate (≥
PR) consistent with a rate of 35%. The first stage of protocol accrual will consist of n=10
patients; to advance to the second protocol accrual stage, RAPA-201 therapy must result in a
tumor response (≥ PR) in at least 2 out of the 10 initial patients.