Medical Hypotheses 7: 43-49, 1981

MALARIOTHERAPY AND CANCER

L e o n a r d B. G r e e n t r e e , 3 1 1 1 E a s t B r o a d S t . , Columbus, Ohio

ABSTRACT

M a l a r i o t h e r a p y merits a c l i n i c a l t r i a l a s a n a d j u v a n t t o
conventional cancer therapy. This p a r t i c u l a r modality of
t r e a t m e n t i s a m o s t p o t e n t s t i m u l u s of m a c r o p h a n e a c t i v i t y .
T h e s e s c a v c n g e r c e l l s a r e w i d e l y b e l i e v e d t o b e an e s s e n -
t i a l a r m i n t h e h o s t ' s immune d e f e n s e s a g a i n s t m a l i g n a n t
d i s e a s e , b o t h a s r e g a r d s t h e p r o c e s s i n g o f a n t i g e n s a n d as
k i l l e r s o f tumor c e l l s . Significant too, malariotherapy,
a s f o r m e r l y u s e d t o e f f e c t i v e l y t r e a t some 1 6 , 0 0 0 p a t i e n t s
with p a r e t i c neurosyphilis i n one i n s t i t u t i o n alone, before
t h e advent o f t h e p e n i c i l l i n age, has proved t o be a par-
t i c u l a r l y s a f e m o d a l i t y of t r e a t m e n t .

Malariotherapy merits a c l i n i c a l t r i a l i n cancer patients

a s an adjuvant t o conventional therapy o f t h i s d?adly
disease. There a r e s o l i d reasons f o r t h i s proposal. F i r s t ,
m a l a r i a l f e v e r i s a most p o t e n t s t i m u l u s of macrophage ac-
t i v i t y (1,2), which is widely b e l i e v e d t o be a n e s s e n t i a l
a r m i n t h e h o s t ' s immune d e f e n s e s a g a i n s t m a l i g n a n t d i s -
e a s e , b o t h a s r e g a r d s tt.r p r o c e s s i n g o f a n t i g e ~ sa n d a s
k i l l e r s of tumor c e l l s ( 3 , 4 , 5 ) . Secondly, malariotherapy,
a s f o r m e r l y u s e d t o e f f e c t i v e l y t r e a t some 1 6 , 0 0 0 p a t i e n t s
i n one i n s t i t u t i o n a l o n e , b e f o r e t h e advent of t h e peni-
c i l l i n era, h a s proved t o b e a p a r t i c u l a r l y s a f e modality
of t r e a t m e n t (6.7).

M a l a r i o t h e r a p y , u s i n g t h e Madagascar s t r a i n of Plasmodium
v i v a x m a l a r i a p a r a s i t e s i s a most p o t e n t immunostimulant i n
t h e s e n s e t h a t i t s t i m u l a t e s t h e production of phagocytic
macrophages t o t h e h i g h e s t l e v e l s , t o enhance t h e h o s t ' s
n a t u r a l d e f e n s e s a g a i n s t h a r m f u l a n t i g e n s , a n d t h e s e may
well include those t h a t cause malignant disease. Stephens
and C h r i s t o p h e r ( 7 ) , f o r exanple, r e p o r t t h a t cacrophage
l e v e l s o f 1 5 p e r c e n t ( i n t h e a b s e n c e of k a l a a z a r ) i s d i -
a g n o s t i c o f m a l a r i a , a n d t h e c o u n t i s n o t u s u a l l y a b o v e 20
percent. Manson-Bahr h i m s e l f ( 7 ) n o t e s i n h i s a u t h o r i t a -
t i v e t e x t b o o k on t r o p i c a l m e d i c i n e , "A h i s t o r y of f e v e r
w i t h a r e l a t i v e l e u c o p e n i a a n d a n i n c r e a s e o f l a r g e mono-
n u c l e a r c e l l s u p to 1 5 p e r c e n t i s s t r o n g c o n f i r m a t o r y
evidence of m a l a r i a ; b u t a l e u c o p e n i a p e r s e does n o t neces-
s a r i l y exclude malaria."

A u n i q u e b i o l o g i c a l h a p p e n i n g makes human b l o o d - i n d u c e d
P . v i v a x m a l a r i a ( m a l a r i o t h e r a p y ) a p a r t i c u l a r l y s a f e modal-
i t y of t r e a t m e n t . H e r e , i n m a l a r i o t h e r a p y , t h e malaria
p a r a s i t e s never invade the l i v e r during t h e i r l i f e cycle
i n man. Hence, flanson-Bahr f u r t h e r s t a t e s t h a t b e c a u s e
t h e s e p a r a s i t e s a r e n o t i n v o l v e d w i t h t h e l i v e r , i n human-
b l o o d induced P.vivax m a l a r i o t h e r a p y , i t is " e x t r a o r d i n a r i -
l y easy" t o d i s i n f e c t t h e p a t i e n t and r e l a p s e s do n o t o c c u r .
On t h e o t h e r h a n d , i n m o s q u i t o - i n d u c e d P . v i v a x m a l a r i a , a n d
t h i s i s obviously most s i g n i f i c a n t , t h e m a l a r i a p a r a s i t e s
-
do i n v a d e t h e l i v e r a f t e r t h e i r b r i e f p a s s a g e i n t h e p e r i -
p h e r a l b l o o d f o l l o w i n g a b i t e by a n i n f e c t e d f e m a l e Anophe-
-
l e s mosquito. Qays l a t e r , i n mosquito-induced P.vivax
m a l a r i a , moat b u t n o t a l l , o f t h e malaria p a r a s i t e s a r e t h e n
r e l e a s e d f r o m t h e l i v e r i n t o t h e c i r c u l a t o r y s y s t e m t o com-
p l e t e t h e i r l i f e c y c l e i n man. But, t h e remaining P.vivax
p a r a s i t e s c o n t i n u e t o h i b e r n a t e i n t h e l i v e r , making i t
d i f f i c u l t t o d i s i n f e c t t h e p a t i e n t a n d r e l a p s e s do o c c u r .
F i g u r e 1.

The i m p o r t a n c e o f p h a g o c y t i c m a c r o p h a g e s i n d i s e a s e i s d r a -
m a t i c a l l y d i s c u s s e d i n The L a n c e t ' s e d i t o r i a l on immuno-
t h e r a p y o f c a n c e r (1976) (8). This e d i t o r i a l prefaces its
remarks on t h e p o s t u l a t e d a n t i - c a n c e r e f f e c t o f p h a g o c y t i c
macrophages by q u o t i n g d i r e c t l y from George Bernard Shaw's
( 9 ) p l a y , "The D o c t o r s Dilemma, ( 1 9 0 6 ) , " T h e r e i s a t b o t t o m
only one genuinely s c i e n t i f i c t r e a t m e n t f o r a l l d i s e a s e s ,
and t h a t i s t o s t i m u l a t e t h e p h a g o c y t e s . Stimulate the
p h a g o c y t e s ; t h e y devour t h e d i s e a s e ; and t h e p a t i e n t r e c o v -
e r s . . . , u n l e s s of c o u r s e h e ' s t o o f a r gone." The L a n c e t
t h e n e d i t o r i a l i z e s , "The a l m o s t - t o o - m e m o r a b l e w o r d s o f t h e
p l a u s i b l e B l o o m f i e l d Bonnington a r e r e - e c h o i n g a g a i n from
t h e many m e e t i n g s w h e r e t h e a n t h e m o f c a n c e r i m m u n o t h e r a p y
can a c c u r a t e l y be heard. T h e r e a s o n s f o r t h i s wave o f en-
thusiasm a r e easy t o understand. F i r s t , t h e r e i s an appre-
c i a t i o n t h a t many human t u m o r s may, i n d e e d , c a r r y a n t i g e n s
t h a t c o u l d p r o v o k e a t h e r a p e u t i c immune r e s p o n s e ; s e c o n d l y ,
t h e r e a r e a v a i l a b l e s e v e r a l i m m u n o p o t e n t i a t o r s which a r e
e a s y t o a d m i n i s t e r a n d w h i c h do n o t c a r r y t h e same t o x i c
r i s k s a s o t h e r forms of c a n c e r t h e r a p y .

S i g n i f i c a n t t o o , enhanced macrophage a c t i v i t y , a s e v i d e n c e d
f r e q u e n t l y by f e v e r , i s , t o a c o n s i d e r a b l e d e g r e e , b u t t h e
h o s t ' s p r o t e c t i v e response t o harmful a n t i g e n s , be they
b a c t e r i a , m a l a r i a p a r a s i t e s , c a n c e r c e l l s o r whatever! Pig-
u r e 2. T h e p o i n t i s made t h a t c l i n i c a l s u c c e s s e s w i t h hy-
p e r t h e r m i a a g a i n s t c a n c e r a r e now b e i n g r e p o r t e d i n t h e
medical l i t e r a t u r e ( 1 0 , l l ) . But a c o m p a r i s o n o f t h e v a r i -
o u s complex p h y s i c a l h y p e r t h e r m i a t e c h n i q u e s p r e s e n t l y
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F i g u r e 1. L i f e cycle of m a l a r i a l p a r a s i t e i n mosquito
a n d man. A d a p t e d f r o m L y n c h ' s M e d i c a l Lab-
. o r a t o r y T e c h n g l o g y , V o l . 1, 1 9 7 6 . ( 2 ) W . B.
S a u n d e r s Compacy. Permission gran t e l .

being used t o t r e a t malignant disease, i n d i c a t e t h a t they

a r e s t i l l very.much i n a p r i m i t i v e s t a g e of development.
C o n v e r s e l y t h a t of m a l a r i o t h e r a p y i s s i m p l e i n c o n c e p t
and broad i n i t s i m p l i c a t i o n s .

W i t h t h e s e t h o u g h t s i n m i n d , i t i s h y p o t h e s i z e d , t h a t ma-
lariotherapy bolsters the host's n a t u r a l defenses against
c a n c e r , by g i v i n g s u c h a m a s s i v e j o l t t o t h e p h a g o c y t i c
macrophage d e f e n s e s t h a t they a t t a c k n o t o n l y t h e m a l a r i a
p a r a s i t e s b u t t h e cancer c e l l s too!

As f o r t h e r o l e o f immunology i n m a l a r i a : In the earlier

s t a g e s o f m a l a r i a l i n f e c t i o n , t h e m u l t i p l i c a t i o n and p a t h -
o g e n i c e f f e c t s of m a l a r i a l p a r a s i r e s a r e c o n t r o l l e d p r i -
m a r i l y by t h e p h a g o c y t i c m a c r o p h a g e s o f the r e t i c u l o e n d o -
t h e l i a l system. This action is, a t f i r s t , non-specific,
and r e p r e s e n t s a n a t u r a l d e f e n s e mechanism i n t h e h o s t .
A s t h e d i s e a s e develops, t h e r e t i c u l o e n d o t h e l i a l system i s
s t i m u l a t e d t o f u r t h e r a c t i v i t y , a s e v i d e n c e d by t h e l o c a l
h y p e r t r o p h y of t h e s p l e e n , t h e main p h a g o c y t i c organ. On
s u b s e q u e n t i n f e c t i o n s , t h i s p h a g o c y t i c a c t i v i t y becomes
more marked and s p e c i f i c (12).

Above a l l , t h e i m p o r t a n c e o f t h e h o s t ' s immune d e f e n s e s

a g a i n s t c a n c e r cannot b e over emphasized. They a r e v e r y
l i k e l y man's m o s t i m p o r t a n t n a t u r a l d e f e n s e a g a i n s t m a l i g -
nant disease. I n cell-mediated immunity, f o r example,
and t h i s b e a r s r e p e a t i n g , macrophages form an e s s e n t i a l
arm i n t h e h o s t ' s immune d e f e n s e s a g a i n s t m a l i g n a n t d i -
s e a s e , b o t h a s r e g a r d s t h e p r o c e s s i n g o f a n t i g e n s and a s
k i l l e r s of tumor c e l l s ( 3 , 4 , 5 ) . Humoral immunity, w i t h
i t s p r o v o c a t i v e , mind-boggling a n t i b o d i e s , a l s o d e s t r o y
tumor c e l l s . But d e s p i t e s i g n i f i c a n t advances during t h e
p a s t few d e c a d e s , o u r t r u e knowledge of t h e mechanism of
humoral immunity i s s t i l l , u n f o r t u n a t e l y , i n an embryonic
s t a g e of development. While t h e s m a l l lymphocyte i s t h e
h e a r t of b o t h s y s t e m s , h e r e o u r t r u e knowledge of i t s
f u n c t i o n i n man, l i k e t h a t o f h u m o r a l i m m u n i t y , i s a l s o
s t i l l i n e a r l y s t a g e of development. That phagocytic
m a c r o p h a g e s f o r m a n e s s e n t i a l arm i n t h e h o s t ' s n a t u r a l
d e f e n s e s a g a i n s t h a r m f u l a n t i g e n s , a p p e a r s t o b e no l ' o n g e r
a m a t t e r f o r s e r i o u s immunologic d e b a t e .

Now, a s f o r m a l a r i o t h e r a p y i t s e l f ( 7 1 , a c o u r s e o f t h e r a p y
c o n s i s t s of e i g h t t o t e n paroxysms of f e v e r , The f i r s t
paroxysm u s u a l l y o c c u r s a p p r o x i m a t e l y o n e t o two d a y s a f t e r
t h e i n t r a v e n o u s i n j e c t i o n o f two t o f o u r m i l l i l i t e r s o f
human b l o o d i n f e c t e d w i t h P . v i v a x m a l a r i a l p a r a s i t e s . A
caution: It i s t e r r i b l y i m p o r t a n t n o t t o u s e P . f a l c i p a r u m
m a l a r i a l p a r a s i t e s by m i s t a k e , b e c a u s e o f t h e i r h i g h mor-
t a l i t y rate. Another caution: I t h a s b e e n known f o r a t
l e a s t 20 y e a r s t h a t a h i g h p e r c e n t a g e o f t h e B l a c k segment
of t h e population a r e r e s i s t a n t t o m a l a r i a f e v e r ; t h a t t h e
e r y t h r o c y t e s o f t h e s e Blacks l a c k t h e Duffy determinants
( F a n~ d / o~ r F ~ w~h i c)h a r e n e e d e d f o r t h e i n v a s i o n o f t h e
r e d b l o o d c e l l s by t h e m a l a r i a p a r a s i t e s ( 1 3 ) . For t h i s
r e a s o n , c l i n i c a l t r i a l s of P.vivax m a l a r i o t h e r a p y on Black
c a n c e r p a t i e n t s , w o u l d o b v i o u s l y , h a v e l i t t l e o r no t h e r -
apeutic value.

I n m a l a r i o t h e r a p y , t h e i n f e c t e d b l o o d w h i c h i s drawn d u r i n g
o r i m m e d i a t e l y a f t e r a paroxysm o f m a l a r i a l f e v e r , i s i m m e -
d i a t e l y d e f i b r i n a t e d and k e p t i n f l a s k s a t a b o u t ' 4 centi-
grade. A t t h i s cold temperature, t h e m a l a r i a l p a r a s i t e s
s u r v i v e f o r a t l e a s t a week. The M a l a r i a l R e f e r e n c e Lab-
o r a t o r y (World H e a l t h O r g a n i z a t i o n ' s (WHO) R e g i o n a l M a l a r i a
~ e f e r e h c eC e n t e r f o r E u r o p e ) s u g g e s t s t h a t t h e f i r s t c a n c e r
p a t i e n t t r e a t e d by m a l a r i o t h e r a p y b e b i t b y m o s q u i t o e i n -
f e c t e d w i t h a proven s a f e S t r a i n of Madagascar P.vivax
malaria p a r a s i t e s , t o a v o i d c o n t a m i n a t i o n .
The London S c h o o l of H y g i e n e and T r o p i c a l M e d i c i n e , w h e r e
t h e Malaria Reference Laboratory is p r e s e n t l y located,
speaks w i t h g r e a t a u t h o r i t y (14). I t was a t t h e l a t t e r
i n s t i t u t i o n w h e r e t h e some 1 6 , 0 0 0 p a t i e n t s w f t h p a r e t i c
n e u r o s y p h i l i s were s u c c e s s f u l l y t r e a t e d w i t h t h e Madagascar
s t r a i n of P , v i v a x malariotherapy (6). The M a l a r i a R e f e r -
e n c e L a b o r a t o r y h a s t h e knowledge o f o n l y o n e c l i n i c a l
t r i a l of malariotherapy i n cancer. It o c c u r r e d a t t h e p r i -
v a t e c a n c e r c l i n i c o f Von P r o f . D r . med, W e r n e r Z a b e l i n
Berchtesgaden i n Bavaria. This c l i n i c a l t r i a l of malario-
t h e r a p y o n t e r m i n a l c a n c e r p a t i e n t s , was p e r f o r m e d u n d e r
t h e d i r e c t s u p e r v i s i o n o f t r a i n e d p e r s o n n e l on l o a n f r o m
t h e M a l a r i a l R e f e r e n c e L a b o r a t o r y , P r o f e s s o r Z a b e l ' s book
(IS): " D i e z u s a t z l i c h e Therapie d e r Geschwufsterkrang-
kungen" s h o u l d b e demand r e a d i n g f o r t h o s e i n t e r e s t e d i n
t h e s u b j e c t under discussion. Zabel concludes, i n t h i s
book, on h i s e x p e r i e n c e s w i t h m a l a r i o t h e r a p y i n c a n c e r a s
follows :

"Anyone who b e g i n s t o d e a l w i t h t h e p r o b l e m
o f m a l a r i o t h e r a p y i n t h e c a r c i n o m a and be-
comes a w a r e of t h e f a i l u r e s i n t h e t h e r a p y
u s e d up t a now, must come t o t h e r e a l i z a -
t i o n t h a t t h e r e is probably no o t h e r pro-
c e d u r e o r method t h a t i s as s u c c e s s f u l as
m a l a r i o t h e r a p y , i f i t i s implemented a t
t h e r i g h t t i m e and i f i t c a n o r i g i n a t e from
v i r u l e n t b l o o d " ( t r a n s l a t e d f r o m t h e Ger-
man ( 1 4 ) .

Environmentally m a l a r i a is a s s o c i a t e d w i t h only one malig-

nant tumor....Burkitt's lymphoma. Burchenal (16) p r e s e n t s
c o n v i n c i n g c l i n i c a l and r e s e a r c h d a t a , i n h i s P r e s i d e n t i a l
a d d r e s s a t t h e American A s s o c i a t i o n f o r Cancer R e s e a r c h ,
t h a t B u r k i t t ' s lymphoma and a c u t e l e u k e m i a a r e somehow re-
l a t e d ; t h a t malaria-induced hypertrophy of the r e t i c u l o e n -
d o t h e l i a l s y s t e m (macrophage e n h a n c i n g ) m i g h t i n c r e a s e t h e
a b i l i t y o f t h e h o s t t o d e v e l o p s p e c i f i c immunity a g a i n s t
both t h e s e malignancies. And, i n t h e c a s e o f a c u t e l e u -
k e m i a , p a r t i c u l a r l y when t h e l e u k e m i a was i'n c o m p l e t e r e -
mission. D a l l f o r f ( 1 7 ) , a p i o n e e r i n t h e d e v e l o p m e n t of
o u r u n d e r s t a n d i n g o f B u r k i t t ' s lymphoma, p o s t u l a t e s t h a t
t h i s malignancy i s an environmental, b i o l o g i c v a r i a n t of
childhood a c u t e lymphoblastic leukemia, w i t h hyperendemic
m a l a r i a a l t e r i n g t h e c l o n e s o f l e u k e m i a c e l l s i n t o becom-
i n g t h o s e o f a much more e a s i l y t r e a t e d a n d c u r a b l e Burk-
i t t ' s lymphoma a t a l a t e r d a t e . If t h e s e o b s e r v a t i o n s
p r o v e t o b e t r u e , m a l a r i o t h e r a p y may i n d e e d b e o f g r e a t
v a l u e i n i m p r o v i n g t h e q u a l i t y o f l i f e , a n d p o s s i b l y ex-
t e n d i n g t h e l i f e span of c h i l d r e n w i t h a c u t e leukemia.
And f o r t h a t m a t t e r , o t h e r m a l i g n a n c i e s t o o .
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Fever

F i g u r e 2. Role of macrophages i n f e v e r . Adapted from

Youmans, P a t e r s o n a n d Sommers: The B i o l o g i -
c a l E a s l s o f I n f e c t i o u s D i s e a s e , 2nd e d . ,
1 9 8 0 . (2)V. B . S a u n d e r s Co. Permission
granted.

CONCLUSION

I n t h i s modern e r a of m i r a c l e s u r g e r y a n d wonder d r u g s , w e
tend t o o v e r l o o k t h e medical and s u r g i c a l accomplishments
of t h e past. Nowhere is t h i s t h o u g h t m o r e a p p l i c a b l e t h a n
i n m a l i g n a n t d i s e a s e , where t h e p o s t u l a t e d a n t i - c a n c e r
macrophage e f f e c t of t h e Madagascar s t r a i n of P.vivax ma-
l a t i o t h e r a p y has been l a r g e l y overlooked. Modern c a n c e r
t e c h n o l o g y s h o u l d b e more c o g n i z a n t o f t h e f a c t t h a t t h e
N o b e l P r i z e f o r M e d i c i n e was a w a r d e d y e a r s a g o t o Wagner
von J a u r e g g (18) f o r h i s s u c c e s s f u l development of malario-
t h e r a p y f o r h i s e f f e c t i v e t r e a t m e n t o f a now rarely e n -
countered d e v a s t a t i n g d i s e a s e , namely, p a r e t i c neurosyphi-
lis

ACKNOWLEDGEMENT

The a u t h o r w i s h e s t o t h a n k t h e M e d i c a l R e s e a r c h D e p a r t m e n t
of t h e R i v e r s i d e Methodist H o s p i t a l f o r its a s s i s t a n c e i n
reviewing t h i s manuscript.
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