NorthWest Biotherapeutics Inc (NWBO)

[sentiment_stocks]

If all the DC are phagocytized (killed off my macrophages) at the injection site, and none actually migrate to lymphs, how can the vaccine be effective??

Well that doesn't appear to be the case. Intradermal (ID) delivery actually works better than Intranodal (IN).

http://clincancerres.aacrjournals.org/content/early/2011/07/19/1078-0432.CCR-11-1261.full.pdf

We found that upon intradermal vaccination the induced T cells were more often able to recognize endogenously processed tumor antigens as compared to intranodal vaccination. Thus, the more laborious and variable intranodal route of administration does not offer an advantage over intradermal vaccination.

In a previous study we found that after IN injection, redistribution to adjacent lymph nodes was only observed when DC were correctly injected into the lymph node, which in that study happened in only ~50% of the cases, despite injection under ultrasound guidance by a highly experienced radiologist.

Although both ID and IN vaccinations induced tumor antigen-specific T cells, ID vaccination more often resulted in the induction of functional T cells recognizing full protein or tumor cells.

We here clearly demonstrated that only a fraction of the tetramer positive T cells appear to be bonafide CTL that can recognize native antigen expressed by Intradermal versus intranodal DC vaccination of melanoma patients tumor cells. In conclusion, the results of our study and other studies, counter-intuitively, suggest that there is no clear advantage of IN vaccination over ID vaccination. This, together with the more technically demanding IN injections, strongly argues in favour of the ID route of administration.

First, injection of DC directly into a lymph node [in other words, intranodal] may lead to a partial destruction of the lymph node architecture(14), which is unfavourable for T cell activation.

Secondly, after IN injection the distribution of DC to distant lymph nodes may partially occur passively via the flow of lymphatic vessels to nearby lymph nodes rather than via active migration of fully matured DC. Thus the percentage of actively migrating DC ending up in the T cell areas may be overestimated after IN administration.

Third, and related to this previous point, [color=red]active migration of DC may be related to post-administration maturation and might thereby increase the capacity of the injected [intradermal] DC to properly activate antigen-specific T cells.[/color]

After ID injection, all DC that enter the lymph nodes are viable and have migrated. They may represent the most mature and hence most potent DC, that express high levels of costimulatory molecules, secrete large amounts of relevant proinflammatory cytokines, and induce the expression of tumor relevant homing receptors on antigen-specific T cells. Thus, ID injected DC may activate potent antigen-specific effector and memory T cells, leading to a strong and long-lasting anti-tumor response.

ID injected DC induce significantly more potent anti-tumor responses when compared with IN injected DC. Although the percentage of DC redistributed to nearby lymph nodes is lower after ID vaccination than after IN vaccination, the number of functional T cells is higher, which is reflected in improved tumor antigen recognition.