Replies to post #15435 on Marker Therapeutics Inc (MRKR)

[lasers]

$TPIV Four Arms

Arm (1)

Experimental: Low dose FRa vaccine
FRa peptide vaccine with GM-CSF adjuvant - single ID administration - monthly vaccinations repeated 6 times followed by boosters every 6 months until recurrence

Biological: Low dose FRa vaccine
165ug per peptide ID injection

Other Name: TPIV200

Arm (2)

Experimental: High dose FRa vaccine
FRa peptide vaccine with GM-CSF adjuvant - triple ID administration - monthly vaccinations repeated 6 times followed by boosters every 6 months until recurrence

Biological: High dose FRa vaccine
500ug per peptide ID injection

Other Name: TPIV200

Arm (3)

Experimental: Low dose FRa vaccine + cyclophosphamide
Cyclophosphamide 300 mg/sqm as a 1 hour IV infusion 3 days prior to first vaccination. Followed by FRa peptide vaccine with GM-CSF adjuvant - ID administration - monthly vaccinations repeated 6 times followed by boosters every 6 months until recurrence
Biological: Low dose FRa vaccine
165ug per peptide ID injection

Other Name: TPIV200
Drug: Cyclophosphamide
IV infusion over 1 hour

Other Name: Cytoxan

Arm (4)

Experimental: High dose FRa vaccine + cyclophosphamide
Cyclophosphamide 300 mg/sqm as a 1 hour IV infusion 3 days prior to first vaccination. Followed by FRa peptide vaccine with GM-CSF adjuvant - ID administration - monthly vaccinations repeated 6 times followed by boosters every 6 months until recurrence
Drug: Cyclophosphamide
IV infusion over 1 hour

Other Name: Cytoxan
Biological: High dose FRa vaccine
500ug per peptide ID injection

Other Name: TPIV200

[esedu]

No, the primary test is on cyclophosphamide. All 4 arms receive vaccine, albeit at 2 different dosages, whereas 2 arms do not receive cyclophosphamide at all.

This is done to more accurately gauge the effect of cyclophosphamide as an immunotherapy priming agent, as it shuts Tregs down. We don't entirely understand how this works, and that's why there's more research to be done. Vaccines based on class II antigens eliciting CD4 stimulation in the past have run into a wall when those same antigens ended up stimulating regulatory T-cells at the same time.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399042/

Regulatory T cells (Tregs) have become an important player in regulating anti-cancer immune responses. In fact, published studies describe a correlation between tumor infiltrating Tregs and poor prognosis. Once called “suppressor T cells”, these T cells evaded isolation due to a lack of known markers that distinguished them from other T cells. However, the biology of these T cells is currently a major focus of immunologic research. Markers have since been discovered that identify these T cells and provide insights into how these T cells are regulated. Despite these advances, much needs to be learned about the sub-sets of Tregs and their specific roles in regulating immune responses. In addition, specific agents that target Tregs are currently unavailable. Cyclophosphamide (CY) has emerged as a clinically feasible agent that can suppress Tregs and allow more effective induction of antitumor immune responses. This review will focus on the use of CY in targeting Tregs to augment cancer vaccine approaches. However, these principles can also be applied to other immunotherapy strategies.

http://meetinglibrary.asco.org/content/148110-156

Background: Folate receptor alpha (FRa) is overexpressed by multiple cancers, including breast and ovarian cancers. Endogenous T-cell immunity to each of five degenerate peptides from FRa (FR30, FR56, FR76, FR113 and FR238) has been demonstrated in both breast and ovarian cancer patients, suggesting the feasibility of targeting FRa via a vaccine approach. Metronomic oral cyclophosphamide (CTX) has been demonstrated to reduce immunosuppressive T regulatory cells (Tregs) and might thereby improve vaccine efficacy. We therefore conducted a Phase I clinical trial testing safety and immunogenicity of a multi-epitope FRa peptide vaccine after 1 cycle of CTX.

Patients in the last trial were on this same chemo drug. It will be interesting to see if patients even need to be on chemotherapy. This study will test that.

Given the known issues of CD4-based vaccines up to this point with regards to increased Treg activity, I'd say cyclophosphamide is pretty essential.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489746/

It is well known that CD4+ helper T cells can directly mediate cytotoxicity against tumor cells.10 However, CD4+ helper T-cell activation generates regulatory T cells (Tregs) which may limit the success of immunotherapy in vivo.11 The exact role of pro-inflammatory interleukin (IL)-17-producing (Th17) cells, which have first been identified in the murine tumor microenvironment, remains to be established.12 According to studies performed in IL-17-deficient mice, Th17 cells may either promote or prevent tumor growth.