Dendritic Cell Therapy in RCC

At a poster presentation session on immunotherapy, one small study caught me eye. As a preface, one set of immune cells is called dendritic cells. They seek out pieces that are flaked off by objects that they deem to be foreign to the body, collect them, swim upstream to the lymph nodes, and deliver the foreign particle to resident T-cells, which are then activated to find the original objects that match the particles and destroy them. The dendritic cells are also called antigen presenting cells, APCs, where the antigen is the foreign particle. The particular T-cells we are concerned with are called antigen specific cytotoxic CD8+ cells. The dendritic cells can also be activated to make them more effective.

Alex Karrlsson from Uppsala University in Sweden presented a poster of a small trial of 12 mRCC patients whose primary tumors were injected with allogeneic dendritic cells (taken from a healthy donor), which were activated to produce an inflammatory reaction and thereby recruit bystander dendritic cells after injection. In Sweden, kidney cancer patients wait for a two-week period from time of diagnosis to nephrectomy, so the investigators injected the tumor twice with a two week interval. The hope was that the dendritic cells would pick up antigens from the tumor and then recruit T-cells, both killer and memory, that would then stick around after nephrectomy and go after the metastasis as well.

The side effects from the injections were mild, mostly a brief fever and chills. After nephrectomy, the pathology report indicated that five tumors had very heavy infiltration of T-cells, one other exhibited “strong” infiltration, five patients moderate, and one weak.

I asked Dr. Karlsson for specific information about each patient, and upon his return to Sweden, he sent me patient details. The following is a report on the poster combined with the patient details. Note that there are two risk factors that are in current use in kidney cancer, one by Dr. Robert Motzer of Memorial Sloan Kettering Cancer Center (MSKCC) and the second by Dr. Daniel Heng (Heng) from the Tom Baker Cancer Center in Alberta, Canada. They categorize patients has having favorable, intermediate, and poor risk.

Some patients were given tyrosine kinase inhibitors (TKIs), sunitinib or pazopanib, after progression. The resected primary tumor in the kidney was resected and examined for CD8+ T-cell penetration. Patients #2, #4, #8, #11, and #12 exhibited “massive” infiltration. Those from Patient #9 had “strong” infiltration, while Patients #1, #3, #7, and #10 had moderate infiltration, and Patient #5 had weak infiltration. No patient had a partial response after nephrectomy. Four patients were given TKIs, three of whom have had ongoing partial responses.     Note that Patient #6 was diagnosed with a second cancer, myeloma, and was dropped from the final analysis.

Patient #1:

Heng/MSKCC intermediate. Clear cell pathology. Multiple (13) lung metastases. Stable disease until 8 months after vaccination when 2 new small lung metastases were observed on the CT-scan. No additional therapy. Very slow and weak overall progression of lung metastases on the scan until 18 months. Thereafter, stablility with no further enlargement. No lung symptoms, works full day as a carpenter 27 months after vaccination. No addition of TKI therapy.

Patient #2:

Heng/MSKCC poor prognosis. Cear cell. At least 8 metastases in the right kidney (parent tumor in the left kidney removed by nephrectomy) and two abdominal mets. Moreover one subcutaneous met in the left breast and in the capillitium. CT-scan 8 months after vaccination exhibited two new small (5 mm) lung mets indicating progression. Also slow progression of kidney met and subcutaneous met. One subcutaneous met was removed 4 weeks after nephrectomy. Good status one year after vaccination leading to partial nephronsparing non-radical surgery of the right kidney. Afterwards new met appeared in the left gluteal region, i.e., the left and right thighs. Additional treatment with pazopanib 17 months after vaccination. Partial response was obtained and is ongoing 6 months after start of pazopanib treatment. There was a lower creatinine reading (better function) in the remaining right kidney despite 8 metastatic lesions in that kidney at diagnosis) after treatment with pazopanib. Patient is still alive 26 months after vaccination.

Patient #3:

Heng/MSKCC poor prognosis. Clear cell. 15 bone mets in the vertebrae, costae, scapula, femur etc). Stable disease with no new mets. Reduction in pain from bone mets. No TKI-treatment. Patient is still alive 21 months after vaccination.

Patient #4:

Heng/MSKCC intermediate. Clear cell. Sarcomatoid differentiation (less than 20%). One solitary met in the lung. Slow enlargement (but not formally progression 4 months after vaccination). Radical metastasectomy performed and since then no signs of tumor recurrence 20 months after vaccination.

Patient #5:

Heng/MSKCC intermediate: Papillary. One abdominal met that has progressed very slowly for 1 year and after that a partial “spontaneous” objective regression without addition of TKIs, 17 months after vaccination.

Patient #6:

No RCC metastases but instead a concomitant myeloma with bone lesions. Evaluated as to safety and immunological response (including CD8+ infiltration), but excluded from survival analysis.

Patient #7:

Heng/MSKCC intermediate. Clear cell. Multiple lung metastases. Extensive sarcomatoid differentiation (> 20%). Rapid progression. Patient died 7.5 months after vaccination.

Patient #8:

Heng/MSKCC poor prognosis. Cear cell. Extensive sarcomatoid differentiation (>20%). Multiple lung metastases and one abdominal metastasis. Mixed response in lung mets 4 months after vaccination. Enlargement of abdominal met. New subcutaneous mets 6 and 8 months after vaccination. Start of sunitinib treatment 9 months after vaccination leading to an objective partial response. Patient is still alive 13 months after vaccination.

Patient #9:

Heng intermediate but MSKCC poor (due to increased LDH levels).Clear cell. 4 new brain metastases and several new liver mets 4 months after vaccination. Very strong objective response (> 60%) at all sites after 6 months of sunitinib treatment. Patient still alive after 12.5 months.

Patient 10:

Heng/MSKCC poor prognosis. Clear cell. Extensive sarcomatoid features. Multiple lung mets. Rapid progress, died 3 months after vaccination.

Patient 11:

Heng/MSKCC poor prognosis. Clear cell. Extensive sarcomatoid features. Multiple lung mets. Rapid progression. Died 5 months after vaccination.

Patient #12:

Heng/MSKCC intermediate. Clear cell. Extensive sarcomatoid features. Multiple lung mets. Slow progression of lung met after 4 months. New additional bone metastasis. Given sunitinib 4 months after vaccination. Stability of bone metastases but some progression of lung metastases. Still alive 9 months after vaccination.

To summarize, three of eleven patients have died. All three had extensive sarcomatoid features in their primary tumor, and, as we know, their prognosis is poor. Of the remaining eight patients, using Heng criteria, five can be categorized as intermediate risk and three poor risk.

Patient       Risk                       Survival

P#1      intermediate                27+ mos.

P#2      poor                               26+ mos.

P#3      poor                                21+ mos.

P#4      intermediate                 20+ mos.

P#5      intermediate                  17+ mos.

P#7      intermediate                 7.5 mos died

P#8      poor + sarcomatoid    13+ mos

P#9      intermediate                12.5+ mos

P#10    poor + sarcomatoid    3 mos died

P#11    poor + sarcomatoid    5 mos died

P#12    intermediate               9+ mos