Allogeneic NKG2DL-targeting CAR γδ T Cells (CTM-N2D) in Advanced Cancers (ANGELICA)

Inclusion Criteria:

* At least 21 years of age
* Provision of signed and dated, written informed consent prior to any study specific procedures, sampling, and analyses (if applicable, the written informed consent may include access to all archival tumour tissue, e.g., diagnostic and/or most recent samples for correlative study)
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 and an estimated life expectancy of greater than 12 weeks
* Females of reproductive age group must be on effective contraception (if sexually active), must not be breast feeding and must have a negative pregnancy test prior to the start of lymphodepletion.
* For the duration of the study and for 1 week after the last study drug administration, sexually active male patients must be willing to use barrier contraception (i.e., condoms) with all sexual partners. Where the sexual partner is a 'woman of child-bearing potential' who is not using effective contraception, the male patients must use a condom (with spermicide) during the study and for 6 months after the last dose of a study drug.
* Adequate hepatic, renal and lung function as demonstrated by any of the following laboratory values:

  * AST or ALT ≤ 3 x ULN
  * Total bilirubin ≤ 1.5 x ULN
  * Glomerular filtration rate (GFR) \> 50 mL/min, as assessed using the Cockroft-Gault formula or 24 h urine creatinine collection
  * SpO2 on room air \> 94%
* Adequate bone marrow reserve as demonstrated by any of the following laboratory values:

  * Absolute neutrophil count (ANC) ≥ 1.0x10\^9/L
  * Platelet count ≥ 75 x 10\^9/L
  * Haemoglobin ≥ 9.0 g/dL
* Patients must have a metastatic cancer resistant to or deemed unsuitable for at least two standard lines of cancer therapy regimens, as part of their management of recurrent/persistent disease.
* Presence of measurable tumour by RECIST 1.1 criteria
* Serum 25 Hydroxyvitamin D total ≥ 20ng/ml
* Have a diagnosis of cancer that is known to express NKG2D ligands

Exclusion Criteria:

* With the exception of alopecia, any unresolved toxicities from prior therapy ≥ the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade 2
* Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to the start of lymphodepletion
* As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, active bleeding diatheses, renal transplant, or active infection including any patient known to have human immunodeficiency virus (HIV) or hepatitis virus. Screening for chronic conditions is not required.
* All HBsAg-positive patients (For HBsAg-negative, but anti-HBc total-positive patients, HBV viral load will be further tested. If HBV viral load is negative, patients may be included.)
* Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel disease (e.g., colitis or Crohn's disease), diverticulitis (with the exception of diverticulosis), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc). The following are exceptions to this criterion:

  * Subjects with vitiligo or alopecia
  * Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  * Any chronic skin condition that does not require systemic therapy
  * Subjects without active disease in the last 5 years may be included but only after consultation with the medical monitor
  * Subjects with celiac disease controlled by diet alone
  * For other autoimmune or inflammatory conditions not specifically mentioned, discuss on case-by-case basis with investigator and medical monitor
* Concurrent severe and/or uncontrolled medical condition (e.g., severe COPD, severe Parkinson's disease, active inflammatory bowel disease) or psychiatric condition (screening for chronic disease is not required)
* Female patients who are breast-feeding or patients of reproductive potential who are not employing an effective method of contraception
* Receiving, or having received during the four weeks prior the start of lymphodepletion, any investigational product
* Treatment with any investigational biological product (e.g., immune check point blockers, antibodies, nanoparticles, experimental) during the four weeks prior the start of lymphodepletion
* Patients who underwent major surgery during the four weeks prior to the start of lymphodepletion
* Radiation (except planned or ongoing palliative radiation to bone outside of the region of measurable disease) during the three weeks prior to the start of Lymphodepletion
* Active infection requiring systemic long-term (\> 2 weeks) treatment with antibiotics, antifungal or antiviral drugs
* Cardiac dysfunction as defined as: Myocardial infarction within six months of study entry, NYHA Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias or reduced LVEF \< 50%.
* Any of the following cardiac criteria:

  * Mean resting corrected QT interval (QTc) \> 470 msec
  * Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block)
  * Uncontrolled hypertension requiring clinical intervention
* Failed dental clearance (for zoledronic acid administration)
* Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements

Subject Withdrawal Criteria

Treatment may continue until one of the following criteria applies:

* Disease progression
* Intercurrent illness that prevents further administration of treatment
* Unacceptable adverse event(s)
* Intolerable non-hematologic toxicities ≥ NCI CTCAE v5.0 Grade 2
* Unmanageable hematologic or non-hematologic toxicities ≥ NCI CTCAE v5.0 Grade 3
* General or specific changes in the patient's condition that renders the patient unsuitable for further treatment at the discretion of the investigator
* Patient who cannot recover from adverse event(s) and lead to treatment delay for \> 4 weeks
* Patient who decides to withdraw from the study