Clinical Trial of SBRT and Systemic Pembrolizumab With or Without Avelumab/Ipilimumab+ Dendritic Cells in Solid Tumors

Inclusion Criteria:

* • Subject has provided written informed consent prior to initiation of any study-specific activities/procedures.

  * Male or female age ≥ 18 years at the time of informed consent.
  * All subjects must have histologically confirmed advanced solid tumors that cannot be completely surgically resected All subjects must have received prior pembrolizumab or nivolumab (with or without cytotoxic chemotherapy or other additional drugs) and fail to respond to this treatment (patients must be documented with stable or progression of disease as their best response to this first-line therapy).
  * Oligometastatic" disease defined by a number of metastatic sites 7
  * ECOG performance status of 0 or 1
  * Patients need to have ≥ 1 metastatic lesion (≥ 10 mm in longest diameter) that can be safely injected by ultrasound-/ CT-guidance, by endo-bronchial ultrasound (EBUS) or even clinically. The lesion should also be amenable for safe biopsy.
  * Injectable metastasis need(s) to be eligible for SBRT
  * Adequate organ function determined within 14 days prior to enrollment
  * Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to enrollment. If urine pregnancy test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  * Subject has a tumor sample (a representative archival tissue sample obtained prior to study participation or newly obtained biopsy). Subject must submit the tumor sample during screening. Subjects with a nonevaluable archival sample may obtain a new biopsy and subjects with a non-evaluable newly obtained biopsy may undergo re-biopsy at the discretion of the investigator.
  * Subjects should have adequate vascular access to undergo a leukapheresis

Exclusion Criteria:

* Known active central nervous system (CNS) metastases. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids \>8 mg/day of methylprednisone or equivalent. The exception does not include leptomeningeal metastasis which is excluded regardless of clinical condition.

  * History or evidence of active autoimmune disease that requires systemic treatment Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  * History or evidence of immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia)
  * History of serious immune related adverse event during treatment with pembrolizumab in first-line
  * History of other malignancy within the past 5 years of enrollment Prior treatment with immune-checkpoint inhibitors (including but not restricted to PD-1, PD-L1 and CTLA-4 blocking mAb) biological cancer therapy, targeted therapy, or major surgery within 28 days prior to enrollment or has not recovered to CTCAE grade 1 or better from adverse event due to cancer therapy administered more than 28 days prior to enrollment. Subjects should not have ongoing grade 3 or 4 immune-related or chemotherapy-related adverse events. Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study Expected to require other cancer therapy while on study with the exception of local radiation treatment to the site of bone and other metastasis for palliative pain management
  * Other investigational procedures while participating in this study are excluded.
  * History or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or syndrome that has required systemic treatment in the past 2 years
  * Evidence of clinically significant immunosuppression
  * Known human immunodeficiency virus (HIV) disease
  * Known acute or chronic hepatitis B or hepatitis C infection
  * Known syphilis infection
  * Female subject is pregnant or breast-feeding, or planning to become pregnant during study treatment and through 6 months after the last dose of study treatment
  * Female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception during study treatment and through 6 months after the last dose of study treatment Postmenopausal (therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.) Male subject who is unwilling to use acceptable method of effective contraception during trial participation and through 6 months after the last dose of study treatment. For this trial, male subjects will be considered to be of non-reproductive potential if they have azoospermia (whether due to having had a vasectomy or due to an underlying medical condition). Note: Acceptable methods of effective contraception are defined in the informed consent form.
  * Subject has known sensitivity to any of the products or components to be administered during dosing.
  * Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge
  * History or evidence of psychiatric, substance abuse, or any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
  * Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or sponsor staff directly involved in this trial, unless prospective institutional review board (IRB)/independent ethics committee (IEC) approval (by chair or designee) is given allowing exception to this criterion for a specific subject.
  * Sexually active subject who is unwilling to use a barrier method (male or female condom) to avoid potential study drug transmission during sexual contact during and within 6 months after study treatment.
  * Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of Graft versus Host Disease.)
  * Has a known history of active tuberculosis.