Armored DLL3-SAVVYZ-IL18 CAR T cells for DLL3+ cancers

Inclusion Criteria:

Participant Inclusion: Collection of T cells (Part A)

* History of DLL3+ neuroendocrine tumors

  * Includes patients with histologically confirmed SCLC, as well other advanced neuroendocrine tumors (NETs), including large cell neuroendocrine carcinomas (LCNECs), gastroenteropancreatic NETs (GEP-NETs), laryngeal NETs, genitourinary (GU) tract NETs, neuroendocrine prostate cancers (NEPCs), gynecological tract NETs, neuroblastomas, salivary NETs, skin NETs, NETs of unknown primary, or other tumor confirmed positive for DLL3 by IHC
  * Any disease status is eligible for collection.
  * DLL3 expression detected by IHC using archival tumor tissue or tissue obtained from a biopsy performed as part of standard clinical care. No new biopsy will be performed solely for DLL3 IHC eligibility testing.
  * Off any immunosuppressive agents for 14 days prior to collection (physiologic dose of corticosteroids is acceptable)

Participant Inclusion: Treatment with DLL3-SAVVYZ-IL18 CAR T cells (Part B)

* Any participant with histologically confirmed SCLC or DLL3 positive tumor who has had one line of approved systemic therapy for limited or extensive stage disease and has progressed or is no longer deriving benefit or standard treatment is no longer tolerable or declines further standard treatment.
* Prior treatment should include an approved platinum-based regimen with/without ICI therapy if applicable to their disease.
* Other advanced tumors are eligible if there is documented progression and/or relapse after appropriate frontline treatment(s) and otherwise meet eligibility criteria.
* At least 1 measurable lesion as defined per modified RECIST 1.1 within 21 days prior to first dose of LDC.
* Age \> 18 years old at the time of signing the informed consent.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
* Minimum life expectancy of 12 weeks.
* Participants previously treated with DLL3-specific therapies (i.e. antibody-drug conjugates, T-cell engager molecules) are permitted.
* History of CNS metastatic disease is permitted if previously treated and stable, defined as no evidence of radiographic progression for at least 4 weeks prior to the first dose of LDC, with any neurologic symptoms returned to baseline. Asymptomatic CNS metastatic disease must also be radiographically stable for at least 4 weeks prior to the first dose of LDC.
* Adequate organ function is required, defined as follows:

  * Hematologic: Hgb \> 9 g/dL, platelets \> 75 x103/ul
  * Hepatic: Serum total bilirubin ≤1.5 mg/dL (unless Gilbert's syndrome), albumin \> 3 g/dL.
  * Hepatic: ALT and AST \< 5 times the upper limit of normal unless thought to be disease-related.
  * Renal: serum creatinine \< 2.0 mg/dL (\> 18 years) or ≤ 2.5 x institutional upper limit of normal (ULN) for age
  * If serum creatinine is outside the normal range, then CrCl \> 40 mL/min/1.73m2 (calculated or estimated) or GFR (mL/min/1.73m2) \> 40% of predicted normal for age.
  * Cardiac: LVEF ≥ 50% by resting echocardiogram
  * Pulmonary: Adequate pulmonary function as assessed by ≥ 92% oxygen saturation on room air by pulse oximetry

Exclusion Criteria:

Participant Exclusion: Collection of T cells (Part A)

* Pregnant or lactating female participants; female participants of reproductive potential, unless they agree to use a highly effective method of contraception or abstain from heterosexual intercourse while receiving study treatment and for at least 12 months after all treatment is finished.
* Sexually active male participants with female partners of reproductive potential, unless they agree to use a condom during intercourse and their female partners use a highly effective method of contraception while the participant is receiving study treatment and for at least 12 months after all treatment is finished.
* Primary CNS malignancies, including glioblastoma multiforme (GBM), are excluded.
* Any systemic anti-cancer therapy within 14 days or at least 4 half lives prior to time of T cell collection, whichever is shorter.
* Radiation therapy completed within 7 days prior to time of T cell collection.
* Uncontrolled, symptomatic, intercurrent infection
* Patients with following cardiac conditions will be excluded:

  * New York Heart Association (NYHA) stage III or IV congestive heart failure.
  * Myocardial infarction ≤ 6 months prior to enrollment.
* Positive serologic test results for HIV.
* Patients with active hepatitis B infection (as manifested by either detectable hepatitis B virus DNA by PCR and/or positivity for hepatitis B surface antigen)
* Patients with active hepatitis C infection (as manifested by detectable hepatitis C virus RNA by PCR)

Participant Exclusion: Treatment with DLL3-SAVVYZ-IL18 CAR T cells (Part B)

* For prior immune related adverse events (irAEs):

  * Unresolved pneumonitis of any grade or history of any grade ICI-mediated CNS toxicities
  * Other unresolved toxicity grade 2 or higher, excluding hypothyroidism.
* Any autoimmune disease requiring active systemic immunosuppression.

  * Use of physiologic steroid replacement for adrenal insufficiency and inhaled corticosteroids are permitted
* Pregnant or lactating female participants; female participants of reproductive potential, unless they agree to use a highly effective method of contraception or abstain from heterosexual intercourse while receiving study treatment and for at least 12 months after all treatment is finished.
* Sexually active male participants with female partners of reproductive potential, unless they agree to use a condom during intercourse and their female partners use a highly effective method of contraception while the participant is receiving study treatment and for at least 12 months after all treatment is finished.
* Primary CNS malignancies, including glioblastoma multiforme (GBM), are excluded
* CNS metastatic disease that is symptomatic (including use of steroids within 7 days prior to the first dose of LDC) or new/enlarging is excluded. Patients with treated brain metastases are permitted if treatment was completed at least 4 weeks prior to the first dose of LDC and the disease has remained radiographically stable for at least 4 weeks prior to the first dose of LDC, with neurologic symptoms returned to baseline.
* Uncontrolled, symptomatic, intercurrent infection
* Patient/parent/guardian unable to give informed consent.
* Any other condition/issue which, in the opinion of the treating physician, would make the patient ineligible for the study; conditions that in the Principal Investigator's opinion might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate.