Trial Title:
Adoptive Cell Therapy Using Cancer Specific CD8+ Tumor Infiltrating Lymphocytes in Adult Patients With Solid Tumors
NCT ID:
NCT05902520
Condition:
HNSCC
Melanoma
Gynecologic Cancer
Colorectal Cancer
Lung Cancer
Urogenital Cancer
Conditions: Official terms:
Urogenital Neoplasms
Conditions: Keywords:
Solid Malignancies
Adoptive Cell Therapy (ACT)
Cancer
T cell
PD-1
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Autologous adoptive T cell therapy provided to three cohorts of patients receiving
supportive subcutaneous IL-2 therapy for one, two ,or three weeks. Each cohort will be
randomized between therapy with DP CD8 TIL or DP CD8 TIL having PD-1 expression reduced
by silencing RNA during invitro cell expansion
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
DP CD8 TIL
Description:
intravenous infusion of T cell suspension
Arm group label:
DP CD8 TIL
Intervention type:
Biological
Intervention name:
DP CD8 TIL KD
Description:
intravenous infusion of T cell suspension
Arm group label:
DP CD8 TIL KD
Intervention type:
Biological
Intervention name:
Low dose IL-2
Description:
Low dose IL-2 delivered subcutaneously for 1, 2 or 3 weeks
Arm group label:
DP CD8 TIL
Arm group label:
DP CD8 TIL KD
Summary:
The subject of this study is the adoptive transfer of selected autologous tumor
infiltrating lymphocytes (TIL) after in vitro expansion for the treatment of solid tumor
malignancies. The TIL selection process is based on evidence showing that CD8+ TIL which
co-express both CD39 and CD103 harbor the bulk of tumor-reactivity and that the remaining
CD8 TIL is mainly composed of non-tumor reactive bystander cells. All of the expanded TIL
that are produced (1-40 billion are expected) will be delivered in the form of a cell
suspension to the participants by intravenous infusion. It is proposed that these
selected TIL will produce a more potent and efficacious treatment of late-stage cancer.
Detailed description:
Our research identified a subpopulation of CD8 tumor infiltrating lymphocytes (TIL)
highly enriched for tumor reactivity that can be identified and isolated based on the
co-expression of CD39 and CD103. The investigators refer to this tumor-reactive cell
population as DP CD8 TIL. The DP CD8 TIL can constitute as few as 2% and up to 70-80% of
the CD8 TIL directly isolated from tumors, suggesting that in any given patient a
substantial percentage of their CD8 TIL can be bystanders lacking tumor specificity. The
CD8 DP TIL were highly enriched for cells that recognize autologous tumor as evidenced by
interferon gamma production, 4-1BB upregulation and autologous tumor cell killing. The
investigators also found that T cell receptors within the CD8 DP TIL population share
very little overlap with the other sub-populations of CD8 TIL, suggesting that they have
a distinct antigen recognition pattern.
The DP CD8 TIL express high levels of PD-1 especially when encountering tumor Ag(s) in
situ. Pre-clinical experiments have shown that the potency of DP CD8 TIL can be enhanced
by decreasing PD-1 checkpoint expression by incubating them with siRNA that targets PD-1.
The investigators hypothesize that transient knockdown of PD-1 expression will enable DP
CD8 TIL to initiate a more effective and persistent anti-tumor response without
increasing toxicity. The investigators refer to DP CD8 TIL after PD-1 knockdown as DP CD8
TIL KD. Although preclinical experiments have shown the value of siRNA modulation of PD-1
in DP T cells, this strategy has not been studied in humans. The main goals of this phase
I first-in-human study are to define toxicity and understand the biology and anti-tumor
activity of DP CD8 TIL alone and with siRNA PD-1 modulation. Thus, the trial is designed
as a randomized comparison of DP CD8 TIL and DP CD8 TIL KD with comprehensive immune
monitoring as detailed below.
Lymphodepleting chemotherapy just before adoptive transfer facilitates proliferation and
persistence of adoptively transferred T cells as has been demonstrated in other adoptive
cellular therapy trials over the last 30 years. Similarly, interleukin-2 (IL-2)
administered after adoptive transfer enhances T-cell proliferation, persistence, and
cytotoxicity. The investigators have also performed pre-clinical experiments confirming
the need for IL-2 after DP CD8 TIL adoptive transfer to achieve maximum antitumor effect
in a human xenograft model. Cyclophosphamide and fludarabine will be given prior to
adoptive transfer of the DP CD8 TIL and high dose IL-2 (600,000 IU/kg IV with a maximum
of 6 doses over 6 days) will be administered starting within 24 hours of the adoptive
transfer followed by subcutaneous IL-2 in dose-escalation cohorts of IL-2, 5 MIU/m2 TIW
starting on day +8 for 1 weeks, 2 weeks or 3 weeks if tolerated.
Criteria for eligibility:
Criteria:
Inclusion Criteria
- Participants must have signed and dated a current IRB/IEC approved written informed
consent form in accordance with regulatory and institutional guidelines. Patients
must have the ability to understand a written informed consent document, and the
willingness to sign it.
- Consent must be obtained before the performance of any protocol related procedures
that are not part of normal patient care.
- Patients must have histologically confirmed advanced solid tumor that is metastatic
or unresectable and who have progression of disease on standard therapy. Historical
pathology reports will suffice to meet this criterion, repeat biopsy confirmation is
not needed.
- Age >18 years
- At least one tumor nodule greater than or equal to 1 cm in long axis diameter
amenable to surgical harvest as an out-patient procedure for DP CD8 TIL production.
- Patients must meet the laboratory criteria below within 28 days prior to the first
dose of study treatment:
- Adequate Bone Marrow Function: WBC >3,000/mcL; Absolute neutrophil count
>1,500/mcL; Hemoglobin > 8 gm/dL; Platelets >100,000/mcL
- Adequate hepatic function: total bilirubin; ≤ 2.0 mg/dL except in patients with
Gilbert's Syndrome who must have a total bilirubin ≤ 3.0 mg/dL; AST(SGOT) < 2.5
X institutional upper limit of normal; ALT(SGPT) < 2.5 X institutional upper
limit of normal
- Adequate renal function: Serum creatinine < 1.5 x ULN, unless creatinine
clearance ≥ 40 mL/min (measured or calculated using the Cockcroft-Gault
formula)
- Women of childbearing potential must not be pregnant and must avoid becoming
pregnant while on treatment and for 6 months following treatment discontinuation.
Men must agree to avoid fathering a child while on treatment and for 6 months
following the last dose of treatment.
- ECOG Performance Status 0-1 or equivalent Karnofsky score at the time of enrollment.
- Patients need to have received at least 1 prior line of systemic therapy before
participation in this protocol and have no therapeutic options with possibility of
cure or durable remission.
- Subjects with squamous cell carcinoma of the head and neck must have received a
platinum containing chemotherapy regimen for treatment of primary tumor in locally
advanced, or metastatic settings and must have received an anti-PD-1/ PD-L1 as
monotherapy or in combination with chemotherapy.
- Subjects with melanoma must have received an anti-PD-1/ PD-L1 inhibitor as
monotherapy or in combination with anti-CTLA-4 inhibitor or anti-PD-1 in combination
with anti-LAG-3 determined to have either primary or secondary CPI resistance.
- Subjects with tumors having known actionable molecular alterations such as BRAF and
MEK for which FDA-approved medications are available must have progressed on
directed molecular therapy.
Exclusion Criteria:
- Active brain metastases or leptomeningeal metastases. Participants with brain
metastases are eligible if these have been treated and there is no MRI evidence of
progression for at least 4 weeks after treatment is complete. There must also be no
requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day
prednisone equivalents). Stable doses of anticonvulsants are allowed. Treatment for
CNS metastases may include stereotactic radiosurgery (e.g. Gamma Knife, Cyber Knife,
or equivalent) or neurosurgical resection. Patients who received whole brain
radiation therapy are not eligible.
- Any condition including medical, emotional, psychiatric, or logistical that, in the
opinion of the Investigator, would preclude the patient from adhering to the
protocol or would increase the risk associated with study participation or study
drug administration or interfere with the interpretation of safety results (e.g., a
condition associated with diarrhea or acute diverticulitis).
- Prior malignancy active within the previous 3 years except for locally curable
cancers that have been apparently cured, such as basal or squamous cell skin cancer,
superficial bladder cancer, or localized carcinoma of the prostate, cervix, or
breast.
- Participants with an active, known or suspected autoimmune disease requiring active
treatment. Participants with type I diabetes mellitus, hypothyroidism requiring only
hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not
requiring systemic treatment, or conditions not expected to recur in the absence of
an external trigger are permitted to enroll.
- Requirement for greater than physiological doses of corticosteroids (> 10 mg daily
prednisone equivalent)
- Requirement for other immunosuppressive medications including but not limited to
anti-TNF antibodies, mycophenylate mofetil and methotrexate. Inhaled, intra-nasal or
topical steroids are permitted in the absence of active autoimmune disease.
- History of organ or tissue transplant that requires systemic use of immune
suppressive agents.
- Active infection requiring systemic therapy within 14 days prior to enrollment.
- Patients who have had chemotherapy, radiotherapy, biologics, other anti-neoplastic
or investigational agents, and/or other antitumor treatment including immunotherapy
within 2 weeks (14 days) of Day -5, or those who have not recovered from adverse
events related to therapies administered more than 4 weeks (28 days) earlier, are
not eligible to enroll. All adverse events related to prior therapy must have
improved to grade 1 or better before study participation.
- Focal radiotherapy (examples include SRS, Palliative or MRI-Linac) completed at
least 2 weeks (14 days) prior to the first dose study treatment are permitted to
enroll.
- Patients with evidence of ischemia on exercise tolerance test, stress thallium
study, or baseline EKG are excluded.
- DLCO, FEV1 or FEV1/FVC less than 65% of predicted due to clinically significant
underlying pulmonary disease. For any pulmonary function test values less than
predicted values, the PI will review, and document the patient's suitability for
high-dose IL-2 therapy.
- Allergy to any of the antibiotics used in the cell production.
- Tumor harvest with no detectable DP CD8 TIL.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Providence Portland Medical Center
Address:
City:
Portland
Zip:
97213
Country:
United States
Status:
Recruiting
Contact:
Last name:
Christopher B Fountain, RN, BSN, OCN
Phone:
503-215-2691
Email:
canrsrchstudies@providence.org
Investigator:
Last name:
Brendan D Curti, MD
Email:
Principal Investigator
Start date:
June 19, 2023
Completion date:
May 19, 2026
Lead sponsor:
Agency:
AgonOx, Inc.
Agency class:
Industry
Collaborator:
Agency:
Phio Pharmaceuticals Inc.
Agency class:
Industry
Collaborator:
Agency:
Providence St Joseph Health
Agency class:
Other
Source:
AgonOx, Inc.
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05902520
