Tetra-punch against solid tumors

Checkpoint blockade therapies has become a gold standard for cancer immunotherapy. However, only in minority of cancer patients did these antibody therapies show significant benefits. Many think that a multi-pronged approach to cancer therapy could tip the balance in favor of anti-tumor therapy.

For sure, data from mouse studies support this line of thinking. For example, this week Nature Medicine published a mouse study showing dramatic benefits of immunotherapy when four different approaches were combined: 

1. Anti-cancer Antibody (A)

2. Long-lived IL-2 (I)

3. Checkpoint PD1 inhibitor (P)

4. Cancer Vaccine (V)

Referred as AIPV this experimental tetra-pronged immunotherapy could clear an established solid tumors (melanoma, breast cancer, adenocarcinoma) in 75%-80% of mice.

Success of AIPV therapy depended mostly on CD8 T cell and NK cells.

Of note, however, frequency of IFN-γ⁺ CD8 T cells did not correlate with anti-tumor effectiveness.

Interestingly, through AIPV could induced endogenous anti-cancer antibodies that transferred protection in naive hosts against intravenous tumor inoculum, B cell deficient mice were still protected against tumors when immunized with AIPV.

Finally, AIPV protected against autochthonous [endogenously developed] tumor in Braf^CA Pten^loxPTyr::Cre^ERT2 mice.

In summary, this mouse study shows that multi pronged immunotherapeutic approach could significantly improve survival rate during cancer therapy. The authors claimed that "AIPV therapy was associated with minimal systemic toxicity, as mice did not show weight loss or substantial elevation in the amounts of liver enzymes in the blood".

Of course, it is difficult to compare outcome in mouse study versus human study. In humans, even single approach with anti-PD1 antibody frequently leads to lung or liver toxicity. Now imagine injecting cancer patients with 4 different immunotherapeutics. So, we have a long way to go before immuntherapy will show the same acceptable-level effectiveness in humans as it does in lab mice.  

David Usharauli 

   

DC vaccine synergizes with αCTLA4/αOX40 against solid tumors

The Objective of any tumor immunotherapy is to achieve tumor-specific T cell response while avoiding any bystander T cell activation. The reason why checkpoint inhibitors, such as αPD-1 and αCTLA4 antibodies work only in a fraction of patients have to do with the fact that only those "responders" have enough pre-existing tumor-specific T cells "responsive" to αPD-1 and αCTLA4 inhibitions. 

Other patients are refractory because their immune system is "blind" or "ignorant" of tumor antigens, i.e. first stage of T cell priming has failed due to lack of antigenic load in DCs (for example, if tumor express few mutated antigens). This situation, however, is potentially reversible with DC vaccines, wherein tumor-specific antigens/epitopes are loaded into DCs. Such "loaded" DCs would then prime T cells which in turn become responsive to checkpoint inhibitors.

So, solid tumor immunotherapy would require multi pronged approach to improve its efficacy. In this regard, I found this new paper in PNAS worth reviewing. Here, the authors showed that combination of "loaded" DC vaccine with αCTLA4/αOX40 treatment were able to overcome dormant state of T cells and allowed efficient control of solid tumors.

Initially, the authors showed that dual αCTLA4/αOX40 antibody treatment allowed substantial expansion of antigen-specific CD8 T cells (in a CD4 T cell-dependent manner).

However, these expanded CD8 T cells were not able to control solid tumor in mice challenged with HER2-expressing TUBO mammary cancinoma cells. However, when αCTLA4/αOX40 antibody treatment were combined with DC vaccine (DEC-205/HER2/PolyI:C), half of tumor challenged mice achieved long-term tumor-free status. 

Now, this is just an example of what potentially could be accomplished with the right concept. In general, OX40 is a complex molecule that has additional role in TH2 immunity, so it is not clear whether this particular combination would be useful in humans. PolyI:C, TLR3 agonist, is not approved for human use either, so it is also not very relevant right now.

In summary, combination of DCs vaccine with checkpoint inhibitors could add missing piece necessary to arm T cells against solid tumors.

David Usharauli

Extracellular matrix (ECM) degradation helps CAR-T cells to control solid tumors

Chimeric antigen receptor-transduced T cells (CAR-T) represent a new and powerful mode of cancer immunotherapy. Results generated so far clearly indicate that CAR-T cells are very good against fluid tumors such as B cell-derived lymphomas. It is not surprising. Anyone working in immunology knows that B cells are one of the best targets for cytotoxic assays. But what about solid tumors? Not so. Why?

New study in Nature Medicine may shed light on this issue. The authors reported that conventional CAR-T cells lack enzyme, heparanase, necessary to degrade ECM that coats solid tumors.

This is a short study, just 4 figures, but the results are very impressive. Initially, the authors showed that long-term culture of ex vivo-expanded (LTE) CAR-T cells down-regulates heparanase activity. Heparanase cleaves heparan sulfate proteoglycans, a part of ECM.

Next, the authors showed that heparanase-transduced CAR-T cells maintain enzyme activity long-term and show improved invasion activity in Matrigel assay. [Of note, the authors results indicate that baseline Matrigel-invasion activity of long-term cultured CAR-T cells is too variable (compare Fig. 1a vs. Fig. 2d; 8% ± 6% vs. 29% ± 18% for the same long-term cultured CAR-T cells)].

Still, in an in vivo assays, heparanse-transduced CAR-T cells showed far superior anti-tumor activity against solid tumors (against neuroblastoma and melanoma) compared to control CAR-T cells. As expected, CAR-T activity against B cell malignancy was not improved by heparanase activity.

In summary, these results suggest that optimization of CAR-T cell therapy against solid tumors would require improving ECM-degradation capacity of CAR-T cells.

David Usharauli