A clinical trial to assess the safety and efficacy of genetically-engineered,
neoantigen-specific Tumor Infiltrating Lymphocytes (TIL) in which the intracellular immune
checkpoint CISH has been inhibited using CRISPR gene editing for the treatment of
Gastro-Intestinal (GI) Cancer.
Tumor Infiltrating Lymphocytes (TIL) have shown efficacy in certain cancers, principally in
melanoma. Efficacy in more common solid tumors has been demonstrated via the selection of
cancer neoantigen-specific TIL. Combination cell surface checkpoint inhibitor therapy has
also been employed in an attempt to enhance the efficacy of these cell therapies. Genetic
engineering of T cells to further increase anti-tumor activity is now possible.
CISH (Cytokine-induced SH2 protein) is a novel intra-cellular immune checkpoint and an
important negative regulator of T-cell signaling and function. The inhibition of CISH in
mouse anti-tumor lymphocytes results in a marked increase in the ability of these lymphocytes
to mediate tumor regression following administration to tumor bearing mice.
Additionally, data in genetically-engineered, neoantigen-specific human T cells in which CISH
was inhibited, showed enhanced TCR functional avidity and increased ability of these T cells
to detect cancer specific mutations and mount robust polyfunctional cytokine immune responses
against their cognate cancer antigens. Thus, these T cells appear to have a significant
advantage in inducing anti-tumor responses compared to wild-type anti-tumor lymphocytes.
The researchers have developed and optimized a CRISPR/Cas9 based strategy for precise and
efficient genetic engineering in primary human T-cells without sacrificing cell viability or
function, allowing for inhibition of a heretofore undruggable intracellular checkpoint.
Thus, in this protocol, the researchers propose to inhibit the gene encoding the
intracellular checkpoint target CISH in lymphocytes from patients with metastatic cancers
that are selected for anti-tumor activity in order to evaluate the safety and efficacy of
genetically engineered T cell therapy for solid tumors in the setting of novel checkpoint
inhibition.
Inclusion Criteria:
- Diagnosis of metastatic gastrointestinal epithelial cancer with progressive disease
following at least one first line standard therapy. When available, archived tissue
from original diagnosis will be obtained for research related testing.
- Must have measurable disease per RECIST 1.1 with at least one lesion identified as
resectable for TIL generation (minimum volume of tumor tissue required is 1 cm^2 as
single mass or fragments) and at least one other lesion meeting the RECIST criteria
for measurable to serve as an indicator of disease response. The location of the tumor
for TIL generation and method used to obtain (i.e. laparoscopy, endoscopic ultra
sound, etc.) will be determined based on an individual patient's disease.
- Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and
asymptomatic are eligible. Lesions that have been treated with stereotactic
radiosurgery must be clinically stable for 1 month after treatment for the patient to
be eligible. Patients with surgically resected brain metastases are eligible. Patients
must not be receiving systemic steroids.
- Brain metastases are assessed using the Response Assessment in Neuro-Oncology Brain
Metastases (RANO-BM) criteria.
- Age ≥ 18 years and ≤ 70 years.
- Clinical performance status of ECOG 0 or 1.
- Serology testing within 3 months of study enrollment (tumor collection):
- Seronegative for HIV antibody. (The investigational treatment being evaluated in
this protocol depends on an intact immune system. Patients who are HIV
seropositive can have decreased immunocompetence and thus may be less responsive
to the study treatment and more susceptible to its toxicities.)
- Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody.
If hepatitis C antibody test is positive, then patient must be tested for the
presence of antigen by RT-PCR and be HCV RNA negative.
- Seronegative for anti-HBc, HBV/HCV/HIV-1 NAT, anti-HTLV-I/II, anti-T.cruzi, West
Nile Virus NAT, anti-CMV, and RPR. (Note: Other blood viral testing may be
required as updated on the FDA website:
https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm095
440.htm#approved)
- Hematology within 14 days of study enrollment:
- Absolute neutrophil count > 1000/mm^3 without the support of filgrastim
- WBC ≥ 3000/mm^3
- Platelet count ≥ 75,000/mm^3
- Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cutoff.
- Adequate organ function within 14 days of study enrollment defined as:
- Serum ALT and AST ≤ 5.0 x ULN
- Serum creatinine ≤ 1.6 mg/dl
- Total bilirubin ≤ to 2.0 mg/dl, except in patients with Gilbert's Syndrome, who
must have a total bilirubin ≤ 3.0 mg/dl.
- More than four weeks must have elapsed since prior systemic therapy at the time the
patient receives the preparative regimen, and acute toxicities must have recovered to
Grade 1 or less (except for toxicities such as alopecia or vitiligo). Disease
appropriate standard therapy is permitted between tumor collection and start of the
fludarabine and cyclophosphamide. Investigational therapy is prohibited.
Note: Patients may have undergone minor surgical procedures within the 3 weeks of the start
of preparative therapy as long as all toxicities have recovered to Grade 1 or less.
- Willing to undergo outpatient non-mobilized leukapheresis (3 hour collection) prior to
the tumor collection
- Agrees to remain in the Twin Cities metropolitan area (within 1 hour drive of the
University of Minnesota) after the CISH KO TILs infusion through the End of Treatment
visit (Day 28)
- Voluntary written consent prior to the performance of any research related procedures
Exclusion Criteria:
- Pregnant or breastfeeding because of the potentially dangerous effects of the
treatment on the fetus or infant. Women of childbearing potential (defined as menses
within previous 12 month and/or FSH ≤ 40 IU/L) must have a negative pregnancy test
(serum or urine) within 7 days of enrollment. A repeat negative pregnancy test is
required within 7 days of beginning the preparative chemotherapy.
- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).
- Concurrent opportunistic infection (The treatment being evaluated in this protocol
depends on an intact immune system. Patients who have decreased immune-competence may
be less responsive to the treatment and more susceptible to its toxicities).
- Active systemic infections requiring anti-infective treatment, coagulation disorders
or any other active major medical illnesses.
- Concurrent systemic steroid therapy.
- History of severe immediate hypersensitivity reaction to cyclophosphamide,
fludarabine, or aldesleukin.
- History of coronary revascularization or ischemic symptoms.
- Documented LVEF ≤ 45% tested in patients:
- Age ≥ 65 years and/or
- With clinically significant atrial and/or ventricular arrhythmias, including but
not limited to: atrial fibrillation, ventricular tachycardia, second- or
third-degree heart block, or have a history of ischemic heart disease and/or
chest pain. Patients < 65 years of age who present with cardiac risk factors
(e.g., diabetes, hypertension, obesity) may undergo cardiac evaluation as noted
above.
- Clinically significant patient history that in the judgment of the PI would compromise
the patient's ability to tolerate high-dose aldesleukin.
- Documented FEV1 ≤ 50% predicted tested in patients with:
- A prolonged history of cigarette smoking (approximately 20 packs/year within the
past 2 years) and/or
- Symptoms of respiratory dysfunction
- Receiving any investigational agents.
Confirmation of Eligibility Prior to CY/FU Start:
Due to a 10-12 week or more delay between study enrollment and the start of study
treatment, the following eligibility criteria must be met:
- Clinical performance status of ECOG 0 or 1
- Hematology within 7 days of starting lymphodepleting chemotherapy:
- Absolute neutrophil count > 1000/mm^3 without the support of filgrastim
- WBC ≥ 3000/mm^3
- Platelet count ≥ 100,000/mm^3
- Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cutoff.
- Adequate organ function within 7 days of starting lymphodepleting chemotherapy:
- Serum ALT and AST ≤ 5.0 x ULN
- Serum creatinine ≤ 1.6 mg/dl
- Total bilirubin ≤ to 2.0 mg/dl, except in patients with Gilbert's Syndrome, who
must have a total bilirubin ≤ 3.0 mg/dl.
- Seronegative for HIV antibody, hepatitis B antigen, and hepatitis C antibody as tested
within 3 months of beginning lymphodepleting chemotherapy. If hepatitis C antibody
test is positive, then patient must be tested for the presence of antigen by RT-PCR
and be HCV RNA negative
- More than four weeks must have elapsed since the last dose of prior systemic therapy
and the start of the lymphodepleting chemotherapy, and acute toxicities must have
recovered to Grade 1 or less (except for toxicities such as alopecia or vitiligo).
- Sexually active females of child-bearing potential and males with female partners of
child-bearing potential must agree to use effective contraception for the duration of
study treatment starting with the 1st dose of fludarabine and for 4 months after the
last dose of aldesleukin. Examples of effective contraception includes an IUD or
implant plus a condom. Women of non-childbearing potential are defined as those who
have no uterus, ligation of the fallopian tubes, or permanent cessation of ovarian
function due to ovarian failure or surgical removal of the ovaries. A woman also is
presumed to be infertile due to natural causes if she has been amenorrheic for > 12
months and/or has an FSH > 40 IU/L.
- Negative pregnancy test within 7 days of starting lymphodepleting chemotherapy in
women of childbearing potential.
- No change in medical status or social situation that would make study participation
not in the best interest of the patient in the opinion of the enrolling investigator.
- Continues to agree to remain in the Twin Cities metropolitan area (within 1 hour drive
of the University of Minnesota) after the CISH KO TILs infusion through the End of
Treatment visit (Day 28)
- Voluntary signed the study treatment consent form within 28 days prior to the start of
the lymphodepleting chemotherapy.
