Background:
- The administration of autologous tumor-infiltrating lymphocytes (TIL) can mediate
complete, durable regressions in 20-25% of participants with metastatic melanoma.
Recent studies have shown that these TIL predominantly recognize unique mutated
neoantigens expressed by the cancer not shared by other melanomas.
- Administration of bulk autologous TIL to participants with a variety of other solid
cancers, including cancers of the gastrointestinal tract and genitourinary tract,
have little if any therapeutic impact.
- Recent studies in the National Cancer Institute Surgery Branch (NCI-SB) have shown
that TIL from non-melanoma solid cancers can also contain T-cells reactive against
non-shared unique mutated or oncoviral neoantigens expressed in the cancer. The
frequency of these T-cells is very low (often < 0.1%) and it is thus difficult to
isolate and grow mutation reactive T-cells to levels required for effective therapy.
- In a single patient with chemo-refractory metastatic cholangiocarcinoma we were able
to grow a relatively pure population of neoantigen reactive TIL and administration
of these cells mediated a near-complete regression of all metastatic disease now
lasting 2.5 years.
- We have developed approaches to identify these rare neoantigen reactive T-cells from
common non-melanoma cancers, to isolate their T-cell receptors (TCR), and to
genetically engineer autologous peripheral blood lymphocytes (PBL) to express these
TCRs with high efficiency. The neoantigen TCR gene-modified cells can recognize and
destroy the autologous cancer in vitro.
- In addition to reactivity to neoantigens derived from nonsynonymous mutations,
T-cells can recognize human papilloma virus (HPV) epitopes in participants with HPV-
induced cancers. The TCR from these reactive cells can be isolated and
retrovirally-transduced into autologous PBL with high efficiency.
- With these techniques, we have isolated a number of TCRs selectively recognizing
shared mutated oncogenes (e.g., KRAS, TP53) or shared oncoviral proteins (e.g. HPV)
in the context of several major histocompatibility complexes (MHC-I and MHC-II).
- This clinical protocol will treat participants with refractory solid cancers using
the adoptive transfer of autologous PBL transduced with genes encoding TCRs that
recognize unique mutated or oncoviral neoantigens expressed by the cancer.
Objectives:
-Primary objective:
--Determine the rate of objective response (using RECIST v1.1 criteria) of participants
with solid cancers who receive pembrolizumab plus autologous PBL (Arm 2) that have been
transduced with genes encoding T-cell receptors that recognize mutated or oncoviral
neoantigens in the autologous cancer
Eligibility:
-Participants must be/have:
- Age greater than or equal to 18 years and less than or equal to 72 years
- Metastatic solid cancer with at least one lesion that can be measured, that falls
into one of five cohorts: (1) gastrointestinal and genitourinary cancers; (2)
breast, ovarian, and other solid cancers; (3) non-small cell lung cancer (NSCLC);
(4) endocrine tumors including neuroendocrine tumors and, (5) multiple myeloma with
solid masses (plasmacytomas).
- Evaluable solid cancer that has recurred following standard chemotherapy or standard
systemic therapy
- Normal basic laboratory values
- No allergies or hypersensitivity to high-dose aldesleukin administration
- No concurrent major medical illnesses or any form of immunodeficiency.
Design:
- Participants will have already undergone resection or biopsy to obtain tumor for
generation of autologous TIL cultures. This will have been conducted under the
NCI-SB cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery
Branch Adoptive Cell Therapy Protocols).
- Exomic sequencing, and often RNA-Seq will be performed to identify the mutations
expressed in the patient s cancer. Multiple autologous TIL cultures will be grown
and tested for reactivity against mutations from the autologous tumor using assays
we have developed that involve the exposure of autologous antigen-presenting cells
to long peptides containing the mutation or tandem mini-genes encoding the mutation.
- T-cell cultures with reactivity against mutations will be identified and the
individual T- cell receptors that recognize the mutation will be synthesized and
used to create a retrovirus for transduction of the TCR into the patient s
autologous PBL.
- Participants that present with tumors expressing oncoviral neoantigens will be
treated with autologous PBLs retrovirally transduced with TCR(s) targeting the
oncoviral neoantigen.
- Participants that present with tumors expressing mutated shared oncogenes (e.g.,
KRAS, TP53) or oncoviral proteins (e.g., HPV) that also express the appropriate
restriction element may be treated with autologous PBLs retrovirally transduced with
TCR(s) previously isolated in the Surgery Branch targeting the shared mutated
antigen. These participants will be administered a cell infusion product of TCRs
targeting mutated shared oncogenes (e.g., KRAS, TP53) or oncoviral proteins (e.g.,
HPV). Their cell infusion product will not include PBL transduced with unique (i.e.,
non-shared) TCR(s).
- Participants will be enrolled into one of five cohorts: (1) metastatic
gastrointestinal and genitourinary cancers; (2) metastatic breast, ovarian, and
other solid cancers; (3) metastatic non-small cell lung cancer (NSCLC); (4)
metastatic endocrine tumors including neuroendocrine tumors and; (5) multiple
myeloma with solid masses (plasmacytomas). Autologous PBL transduced with TCR(s)
targeting neoantigens (mutated shared oncogenes e.g., TP53, KRAS, individual
non-synonymous mutations , or oncoviral proteins) will then be expanded to large
numbers using our standard rapid expansion protocol.
- Participants enrolled on Arm 1 and Arm 2 will receive a non-myeloablative,
lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine
followed by the infusion of autologous transduced PBL and high-dose aldesleukin. At
the discretion of the Principal Investigator (PI), participants enrolled in Cohort 3
(NSCLC) may receive low-dose aldesleukin.
- Participants enrolled on Arm 2 will receive pembrolizumab prior to cell
administration and three additional doses every three weeks following the cell
infusion. Participants who have experienced major organ toxicity due to previous
treatment with pembrolizumab (or equivalent PD-1/PD-L1 blockade) will be enrolled on
Arm 1.
- Clinical and immunologic response will be evaluated about 4-6 weeks after cell
infusion and periodically thereafter.
- It is anticipated that approximately one participant per month may enroll on the
trial for each of the four histologic cohorts for Arm 2. There will be a limit of 15
participants per cohort enrolled on Arm 1 (75 participants for Arm 1), and accrual
of up to 4 x 50 = 200 total evaluable participants on Arm 2. It is expected that
once full manufacturing capability is reached, the accrual may be completed in
approximately 4-5 years. In order to allow for a small number of inevaluable
participants, the accrual ceiling will be set to 285.